Corticosteroids for pneumonia.

BACKGROUND: Pneumonia is a common and potentially serious illness. Corticosteroids have been suggested for the treatment of different types of infection, however their role in the treatment of pneumonia remains unclear. This is an update of a review published in 2011.

OBJECTIVES: To assess the efficacy and safety of corticosteroids in the treatment of pneumonia.

SEARCH METHODS: We searched the Cochrane Acute Respiratory Infections Group’s Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS on 3 March 2017, together with relevant conference proceedings and references of identified trials. We also searched three trials registers for ongoing and unpublished trials.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed systemic corticosteroid therapy, given as adjunct to antibiotic treatment, versus placebo or no corticosteroids for adults and children with pneumonia.

DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. We estimated risk ratios (RR) with 95% confidence intervals (CI) and pooled data using the Mantel-Haenszel fixed-effect model when possible.

MAIN RESULTS: We included 17 RCTs comprising a total of 2264 participants; 13 RCTs included 1954 adult participants, and four RCTs included 310 children. This update included 12 new studies, excluded one previously included study, and excluded five new trials. One trial awaits classification.All trials limited inclusion to inpatients with community-acquired pneumonia (CAP), with or without healthcare-associated pneumonia (HCAP). We assessed the risk of selection bias and attrition bias as low or unclear overall. We assessed performance bias risk as low for nine trials, unclear for one trial, and high for seven trials. We assessed reporting bias risk as low for three trials and high for the remaining 14 trials.Corticosteroids significantly reduced mortality in adults with severe pneumonia (RR 0.58, 95% CI 0.40 to 0.84; moderate-quality evidence), but not in adults with non-severe pneumonia (RR 0.95, 95% CI 0.45 to 2.00). Early clinical failure rates (defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8) were significantly reduced with corticosteroids in people with severe and non-severe pneumonia (RR 0.32, 95% CI 0.15 to 0.7; and RR 0.68, 95% CI 0.56 to 0.83, respectively; high-quality evidence). Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications.Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates (defined as for adults, RR 0.41, 95% CI 0.24 to 0.70; high-quality evidence) based on two small, clinically heterogeneous trials, and reduced time to clinical cure.Hyperglycaemia was significantly more common in adults treated with corticosteroids (RR 1.72, 95% CI 1.38 to 2.14). There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections (RR 1.19, 95% CI 0.73 to 1.93).

AUTHORS’ CONCLUSIONS: Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits.

Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes

This Cochrane Review examines the effects of different policies for clamping the umbilical cord after birth for babies born at term. It compares early cord clamping, which usually takes place within 60 seconds of birth, versus later clamping that usually involves clamping the cord more than one minute after birth or when cord pulsation has ceased.

In the past, the umbilical cord has usually been clamped shortly following the birth of the baby, as part of the active management of the third stage of labour. This strategy might also involve the infant being placed on the mother’s abdomen, put to the breast or more closely examined on a warmed cot if resuscitation was required. However, more recent guidelines for management of the third stage of labour no longer recommend immediate cord clamping, and later clamping of the umbilical cord might take place when cord pulsation has ceased or beyond the first minute following the birth of the baby. However, there is ongoing uncertainty about the relative benefits, or harms, of the two approaches. There have been concerns that late cord clamping might increase the mother’s risk of a postpartum haemorrhage, that could outweigh potential benefits to the baby of delaying clamping which might arise from the extra time for a transfer of the fetal blood in the placenta to the infant at the time of birth. This placental transfusion can provide the infant with an additional 30% more blood volume and up to 60% more red blood cells.

The authors of this updated Cochrane Review searched the Cochrane Pregnancy and Childbirth Group’s Trials Register in February 2013. This Register is maintained through electronic searching of the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE; along with dedicated searching of dozens of journals and the proceedings of major conferences. After checking 74 reports representing 58 studies, they excluded 37 studies and included 15 in the review. A further 4 studies are awaiting assessment and 2 ongoing studies were also identified. The 15 included randomized trials recruited a total of 3911 mother and baby pairs.

The primary outcome measures for the review included maternal death and severe maternal morbidity as a composite outcome, but none of the included studies reported data on these. However, in the five trials (2066 women) that reported another of the primary outcome measures, severe postpartum haemorrhage (PPH) (blood loss of ≥1000 ml blood), there were no significant differences between early versus late cord clamping (risk ratio (RR): 1.04, 95% confidence interval (CI): 0.65 to 1.65). There were also no significant differences for PPH of ≥500 ml (RR: 1.17, 95% CI: 0.94 to 1.44, 5 trials, 2260 women), mean blood loss (mean difference (MD): 5.11 ml, 95% CI: -23.18 to 33.39, 2 trials, 1345 women), or maternal haemoglobin values at 24 to 72 hours after the birth (MD: -0.12 g/dl, 95% CI: -0.30 to 0.06, 3 trials, 1128 women).

The primary outcome measure for the babies was neonatal mortality but data were only available from two trials, in which four of the 381 babies died. There was no significant difference between the early and late cord clamping groups (RR: 0.37, 95% CI: 0.04 to 3.41). Other infant outcomes with no significant differences between early and late cord clamping were Apgar scores below 7 at 5 minutes (RR: 1.23, 95% CI: 0.73 to 2.07, 2 trials, 1342 neonates), and admission to a special care baby nursery or neonatal intensive care unit (RR: 0.79, 95% CI: 0.48 to 1.31, 4 trials, 1675 infants). Fewer infants in the early cord clamping group required phototherapy for jaundice than in the late cord clamping group (RR: 0.62, 95% CI: 0.41 to 0.96, 7 trials, 2324 infants), haemoglobin concentration was significantly lower in the early cord clamping group at 24 to 48 hours (MD: -1.49 g/dl, 95% CI: -1.78 to -1.21, 4 trials, 884 infants) and infants in the early cord clamping were more than twice as likely to be iron deficient at three to six months (RR: 2.65, 95% CI: 1.04 to 6.73, 5 trials, 1152 infants. On the negative side for late cord clamping, babies in the early clamping group were less likely to require phototherapy for jaundice (RR: 0.62, 95% CI: 0.41 to 0.96, 7 trials, 2324 infants). Unlike many of the outcomes of interest to the reviewers, birthweight was reported across a large proportion of the studies. The mean weight of babies was found to be significantly higher in the late cord clamping group (MD: 101 g increase, 95% CI 45 to 157, 12 trials, 3139 infants) but with high statistical heterogeneity (I2: 62%).

The authors write that a more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of the growing evidence that delayed cord clamping increases early haemoglobin concentrations and iron stores in infants. They conclude that delayed cord clamping is likely to be beneficial, as long as access to treatment for jaundice requiring phototherapy is available.

Soure: Cochrane Library

Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis.


Objective To evaluate risk factors for severe outcomes in patients with seasonal and pandemic influenza.

Design Systematic review.

Study selection Observational studies reporting on risk factor-outcome combinations of interest in participants with influenza. Outcomes included death, ventilator support, admission to hospital, admission to an intensive care unit, pneumonia, and composite outcomes.

Data sources Medline, Embase, CINAHL, Global Health, and the Cochrane Central Register of Controlled Trials to March 2011.

Risk of bias assessment Newcastle-Ottawa scale to assess the risk of bias. GRADE framework to evaluate the quality of evidence.

Results 63 537 articles were identified of which 234 with a total of 610 782 participants met the inclusion criteria. The evidence supporting risk factors for severe outcomes of influenza ranged from being limited to absent. This was particularly relevant for the relative lack of data for non-2009 H1N1 pandemics and for seasonal influenza studies. Limitations in the published literature included lack of power and lack of adjustment for confounders was widespread: adjusted risk estimates were provided for only 5% of risk factor-outcome comparisons in 39 of 260 (15%) studies. The level of evidence was low for “any risk factor” (odds ratio for mortality 2.77, 95% confidence interval 1.90 to 4.05 for pandemic influenza and 2.04, 1.74 to 2.39 for seasonal influenza), obesity (2.74, 1.56 to 4.80 and 30.1, 1.74 to 2.39), cardiovascular diseases (2.92, 1.76 to 4.86 and 1.97, 1.06 to 3.67), and neuromuscular disease (2.68, 1.91 to 3.75 and 3.21, 1.84 to 5.58). The level of evidence was very low for all other risk factors. Some well accepted risk factors such as pregnancy and belonging to an ethnic minority group could not be identified as risk factors. In contrast, women who were less than four weeks post partum had a significantly increased risk of death from pandemic influenza (4.43, 1.24 to 15.81).

Conclusion The level of evidence to support risk factors for influenza related complications is low and some well accepted risk factors, including pregnancy and ethnicity, could not be confirmed as risks. Rigorous and adequately powered studies are needed.

What is already known on this topic

  • Certain patient populations are thought to be at higher risk for developing complicated or severe influenza illness
  • These groups are prioritised for vaccination as well as for antiviral treatment
  • The quantity and quality of evidence on risk factors for developing complicated or severe influenza illness is limited
  • While some risk factors could be corroborated, evidence to support other, well established risk factors for severe outcomes could not be found

What this study adds

Source: BMJ

Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation.



Anticoagulant treatment with vitamin K antagonists (VKAs) is aimed at preventing thromboembolic complications and has been the therapy of choice for most people with non-valvular atrial fibrillation (AF) for many decades. A new class of anticoagulants, the factor Xa inhibitors, appear to have several pharmacological and practical advantages over VKAs.


To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for the prevention of cerebral or systemic embolic events in people with AF.


We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (June 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE (1950 to April 2013) and EMBASE (1980 to April 2013). In an effort to identify further published, unpublished and ongoing trials we searched trials registers and Google Scholar (July 2012). We also screened reference lists and contacted pharmaceutical companies, authors and sponsors of relevant published trials.


Randomised controlled trials that directly compared the effects of long-term treatment (more than four weeks) with factor Xa inhibitors and VKAs for the prevention of cerebral and systemic embolism in patients with AF. We included patients with and without a previous stroke or TIA.


The primary efficacy outcome was the composite endpoint of all strokes and other systemic embolic events. Two authors independently assessed trial quality and the risk of bias, and extracted data. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. However, in the case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects and performed a pre-specified sensitivity analysis excluding any fully open-label studies.


We included data from 42,084 participants randomised into 10 trials. All participants had a confirmed diagnosis of AF (or atrial flutter) and were deemed by the randomising physician to be eligible for long-term anticoagulant treatment with a VKA (warfarin) with a target International Normalised Ratio (INR) of 2.0 to 3.0 in most patients. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux or rivaroxaban. Four trials were double-masked, five partially-masked (that is different doses of factor Xa inhibitor administered double-masked and warfarin administered open-label) and one was open-label. Median duration of follow-up ranged from 12 weeks to 1.9 years.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in nine of the included studies (40,777 participants). Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin (OR 0.81, 95% CI 0.72 to 0.91). We also analysed both components of this composite endpoint separately: treatment with a factor Xa inhibitor significantly decreased both the number of ischaemic and haemorrhagic strokes (OR 0.78, 95% CI 0.69 to 0.89) and the number of systemic embolic events (OR 0.53, 95% CI 0.32 to 0.87).All of the included studies (42,078 participants) reported the number of major bleedings. Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.89, 95% CI 0.81 to 0.98). There was, however, statistically significant and high heterogeneity (I² = 81%) and an analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings (OR 0.92, 95% CI 0.63 to 1.34). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.84, 95% CI 0.76 to 0.92) but moderate heterogeneity was still observed (I² = 65%). A similar sensitivity analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings in patients treated with factor Xa inhibitors (OR 0.78, 95% CI 0.57 to 1.05). Part of the observed heterogeneity can thus be explained by the increased risk of major bleedings in the factor Xa treatment arm in the single included open-label study, which studied idraparinux. Other heterogeneity might be explained by differences in baseline bleeding risks in the two largest trials of apixaban and rivaroxaban that we included in this review.Data on intracranial haemorrhages (ICHs) were reported in eight studies (39,638 participants). Treatment with a factor Xa inhibitor significantly reduced the risk of ICH compared with warfarin (OR 0.56, 95% CI 0.45 to 0.70). Again, we observed statistically significant heterogeneity (I² = 60%). The pre-specified sensitivity analysis excluding the open-label study showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.51, 95% CI 0.41 to 0.64), without any sign of statistical heterogeneity (I² = 0%).The number of patients who died from any cause was reported in six studies (38,924 participants). Treatment with a factor Xa inhibitor significantly reduced the number of all-cause deaths compared with warfarin (OR 0.88, 95% 0.81 to 0.97).


Factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in patients with AF. Factor Xa inhibitors also seem to reduce the number of major bleedings and ICHs compared with warfarin, though the evidence for a reduction of major bleedings is somewhat less robust. There is currently no conclusive evidence to determine which factor Xa inhibitor is more effective and safer for long-term anticoagulant treatment of patients with AF as head-to-head studies of the different factor Xa inhibitors have not yet been performed.

Source: PMID


Ultrasonographically guided peripheral intravenous cannulation of children and adults: a systematic review and meta-analysis. .

Peripheral intravenous cannulation is procedurally challenging and painful. We perform a systematic review to evaluate ultrasonographic guidance as an aid to peripheral intravenous cannulation.

METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science,, and We included randomized trials evaluating ultrasonographically guided peripheral intravenous cannulation and reporting risk of peripheral intravenous cannulation failure, number of attempts, procedure time, or time from randomization to peripheral intravenous cannulation. We separately analyzed pediatric and adult data and emergency department (ED), ICU, and operating room data. Quality assessment used the Cochrane Risk of Bias Tool.
RESULTS: We identified 4,664 citations, assessed 403 full texts for eligibility, and included 9 trials. Five had low risk, 1 high risk, and 3 unclear risk of bias. A pediatric ED trial found that ultrasonography decreased mean difference (MD) in the number of attempts (MD -2.00; 95% confidence interval [CI] -2.73 to -1.27) and procedure time (MD -8.10 minutes; 95% CI -12.48 to -3.72 minutes). In an operating room pediatric trial, ultrasonography decreased risk of first-attempt failure (risk ratio 0.23; 95% CI 0.08 to 0.69), number of attempts (MD -1.50; 95% CI -2.52 to -0.48), and procedure time (MD -5.95; 95% CI -10.21 to -1.69). Meta-analysis of adult ED trials suggests that ultrasonography decreases the number of attempts (MD -0.43; 95% CI -0.81 to -0.05). Ultrasonography decreased risk of failure (risk ratio 0.47; 95% CI 0.26 to 0.87) in an adult ICU trial.
CONCLUSION: Ultrasonography may decrease peripheral intravenous cannulation attempts and procedure time in children in ED and operating room settings. Few outcomes reached statistical significance. Larger well-controlled trials are needed.

Source: Annals of Emergency Medicine.


New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding.


Background & Aims A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients’ risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC.

Methods We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I2test.

Results The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07–1.97), but there was substantial heterogeneity among studies (I2, 61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91–1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31–1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03–2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58–10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56–2.73), the OR for dabigatran was 1.58 (95% CI, 1.29–1.93), the OR for edoxaban was 0.31 (95% CI, 0.01–7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21–1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00–1.34), with similar trends among subgroups.

Conclusions Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.


Gastrointestinal bleeding (GIB) is a serious medical condition that causes considerable morbidity and mortality (5%–15%) and poses an enormous burden on global health care use.[1] The mean hospital costs are reported to range from $2500 to $7300 for upper GIB, $4800 for lower GIB, and around $40,000 for small-bowel bleeding.[2] The expanding indications and increasingly intensive treatment with antithrombotic agents have increased the burden of GIB related to these agents.[3] Antiplatelet agents (eg, aspirin and thienopyridine derivatives) can give rise to GIB by producing ulcers and erosions throughout the gastrointestinal tract. Anticoagulants (ie, vitamin K antagonists [VKA]) and heparins might precipitate bleeding from pre-existing lesions.[4] The relative risk of GIB varies from 1.5 for low-dose aspirin compared with nonuse[5]and more than 5 for the combination of aspirin and VKA.[3] In light of their efficacy, the increased risk of bleeding induced by the therapy is acceptable. Two important limitations of the traditional antithrombotic agents comprise the need for international normalized ratio monitoring with tailored VKA dosing, or subcutaneous administration of low-molecular-weight heparins (LMWH).

New oral anticoagulants (nOAC) (eg, factor IIa [thrombin] or factor Xa inhibitors) have been developed and theoretically lack these limitations.[6–8] These drugs are as effective as current therapy. Some randomized controlled trials (RCTs) reported an isolated higher GIB risk,[9,10] which is potentially fatal, costly, and avoidable. It is therefore important to carefully review the literature on GIB risk attributable to use of nOAC. This is particularly relevant because patients on nOAC often use concomitant low-dose aspirin and/or thienopyridines, which may add substantially to the as yet unknown GIB risk. Furthermore, in contrast with the traditional OAC, no clinically tested antidote is currently available for the novel agents, hampering therapeutic options in case of GIB.[11] For these reasons, we conducted a systematic review focusing on the risk of GIB of all nOAC. Because not all trials separately reported GIB risk, we also reviewed the evidence on risk of clinically relevant bleeding associated with nOAC use.


Study Definitions

The exposure of interest was defined as the (approximated) indication-specific recommended daily dose of the nOAC either by the European Medicines Agency[12] or the Food and Drug Administration[13] for registered nOAC. When nOAC was not registered for the indication for which it was studied, the indication-specific daily dose was defined according to the pharmaceutical manufacturer.

Standard care was defined as either low-molecular-weight heparin, vitamin K antagonist, antiplatelet therapy, or no (additional) therapy/placebo, depending on the (inter)national guidelines regarding antithrombotic therapy for the concerning indication.

The primary outcome of this systematic review was the risk of GIB. GIB was considered as at least one episode of clinically apparent hematemesis (frank blood or coffee-ground material that tested positive for blood), melena, or spontaneous rectal bleeding (if more than a few spots) or endoscopically confirmed bleeding, and was judged as major or clinically relevant nonmajor depending on the severity.[14]

The secondary outcome was the risk of clinically relevant bleeding (encompassing both major bleeding and clinically relevant nonmajor bleeding). Major bleeding and clinically relevant nonmajor bleeding in the included studies were defined by the following: (1) the International Society on Thrombosis and Haemostasis[15,16] (2) the Thrombolysis In Myocardial Infarction,[17] or (3) an adjustment of the International Society on Thrombosis and Haemostasis definition (see Table 1 for exact definitions).

Data Sources and Searches

A comprehensive literature search was conducted to identify RCTs reporting GIB or clinically relevant bleeding in patients receiving nOAC compared with standard treatment. Medline with PubMed as interface, EMbase, and the Cochrane Central Register of Controlled Trials were searched from inception to July 2012. Medical subject heading terms and keywords used to identify RCTs included “apixaban,” “rivaroxaban,” “dabigatran,” “edoxaban,” “betrixaban,” “humans,” and “randomized controlled trial.” No language restrictions were applied. The electronic search strategy was complemented by a manual review of reference lists of included articles. References of recent reviews on nOAC also were examined.[11,18-23]

Study Selection

Search results were combined and duplicates were removed. Studies were first screened based on title and abstract for relevance, after which the full text was reviewed. This was performed independently by 2 reviewers (I.L.H. and V.E.V.). Inter-rater agreement was assessed using the k statistic. Any discrepancies were resolved by consensus, contacting a third author (E.T.T.L.T.). Studies had to meet the following inclusion criteria: (1) the study compared nOAC with the current standard care in a randomized setting; (2) results included bleeding events as a safety outcome; (3) the study was conducted in the target population of the drug and not in healthy volunteers; and (4) it was published as a full-text article. If any of the 4 criteria were not met, the study was excluded. If data from the same study were published in multiple languages, data from the English article were extracted. In case of suspicion of double reporting of the same patient populations, data from the main publication were extracted.

Data Extraction

The included studies were divided by clinical indication of anticoagulant therapy into the following indication groups: (1) prevention of stroke and systemic embolism in patients with atrial fibrillation (AF); (2) prevention of venous thromboembolism after orthopedic surgery (OS); (3) prevention of venous thromboembolism in medically ill patients; (4) treatment of acute deep vein thrombosis (DVT) or pulmonary embolism (PE); and (5) treatment of acute coronary syndrome (ACS). For each included study, we recorded the number of trial participants, follow-up period, and the number of patients who developed the primary safety end points for both treatment arms. The mean age at baseline and the percentage of males were assessed, as well as other characteristics of the study population such as relevant concomitant medications that may affect bleeding risk. This was performed independently by 2 authors (I.L.H. and V.E.V.). Finally, we contacted the main investigator for missing data. Furthermore, given the heterogeneity of the studies, an individual patient data analysis was attempted. All authors were contacted and requested to provide individual patient data. We received responses from 7 of 23 authors (covering 12 of 43 studies). Unfortunately, no one agreed to share this information.

Quality Assessment

The quality of included studies was assessed according to the Cochrane Reviewers’ Handbook.[24] Both manuscript and protocol, if available online, were scanned for relevant information on quality.

Data Synthesis and Analysis

Odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated for each RCT and were the bases for the meta-analyses. To include studies with null events in either the active treatment arm or the standard care arm, 0.5 events were added to all cells with study results. In case of null events in both arms, no OR was calculated. To quantify how many patients needed to be exposed to nOAC therapy to cause one additional GIB compared with standard care the number needed to harm (NNH) was assessed.

To explore between-study variability the Cochran Q test and the Higgins I2 test for heterogeneity were used. Significant heterogeneity was assumed when the Cochran Q P value was less than .10 and the I2 was greater than 50%. To reduce the impact of heterogeneity, we used a random-effects model in these cases.

To account for possible sources of heterogeneity, we performed prespecified subgroup analyses according to type of nOAC and indication. Heterogeneity between subgroups was evaluated further by a post hoc meta-regression analysis by indication, type of nOAC, and comparator. Comprehensive meta-analysis v2.0 (Biostat, Englewood, NJ) was used to perform the meta-analysis. Meta-regression was performed using PASW statistics 20.0 for Windows (SPSS, IBM, Armonk, New York).

Sensitivity analysis was performed to exclude studies that compared the bleeding risk of nOAC use with the use of placebo as standard care because this intervention is unlikely to increase bleeding risk. Because we only included published data, publication bias was quantified with the Egger regression test, with the results considered to indicate publication bias when the P value was less than .10. In addition, funnel plots were examined for asymmetry.




Our initial search identified 375 records (Figure 1A). A total of 42 studies were eligible for inclusion. The agreement between reviewers for trial inclusion was excellent (κ, 0.94). The clinical indication comprised AF in 8 studies,[9,10,25–30] OS in 21 studies, [31–51]medically ill patients in 2 studies,[52,53] DVT/PE in 6 studies (reporting on 7 trials),[54–59] and ACS in 5 studies (Figure 1B).[60-64]

To gain insight into the performance per drug, the information on bleeding risk was summarized per individual drug (Figure 1C). Rivaroxaban was studied most frequently (15 studies reporting on 16 trials),[10,32–35,39–41,44,54,55,58,59,61,63] followed by apixaban (12 trials),[28–30,38,45,48,49,52,53,56,60,62] dabigatran (10 trials),[9,25,31,36,37,42,46,51,57,64] edoxaban (4 trials),[26,27,47,50] and betrixaban (1 trial).[43] The main characteristics of the 43 included trials are summarized in Supplementary Tables 1–5.

Study Characteristics

A total of 151,578 patients were included in the 43 trials. Duration of follow-up evaluation ranged from 3 weeks to 31 months, with shorter durations of follow-up evaluation for the OS studies and longer durations for AF studies. Patients with a recent history of peptic ulcer disease or patients with an otherwise increased risk of GIB (eg, patients with a thrombocytopenia or coagulation disorder) were excluded in all 43 trials. Concomitant use of any co-medication affecting coagulation was prohibited in 19% of trials, only low-dose aspirin (<160 mg) was allowed in 14%, only short-acting nonsteroidal anti-inflammatory drugs (NSAIDs) (<17 hours) were allowed in 16%, and short-acting NSAIDs/cyclooxygenase-2 inhibitors and/or low-dose aspirin and/or thienopyridines was allowed in 44%, mostly with the addition that it was discouraged. Information on the allowance of antithrombotic co-medication was absent in 7% of trials (Supplementary Tables 1–5).

Study Exposure

First, the risk estimates from each study were pooled by indication because the registered/recommended dose for each individual nOAC differs per indication (Supplementary Table 6). A total of 125,354 patients (83%) were enrolled in the therapeutic arms relevant to this review. Of the 8 trials on AF, 7 trials compared one of the novel agents with dose-adjusted warfarin. Of the 21 trials on thromboprophylaxis after OS, 19 compared a nOAC with LMWH (Supplementary Tables 1–5). All trials, except one trial[58] on DVT/PE treatment, compared a nOAC with LMWH followed by VKA. The trials on treatment of ACS compared nOAC with placebo, in addition to standard (double) antiplatelet therapy.

Publication Bias

The result of the Egger regression test for publication bias was not significant (intercept, 0.7; 95% CI, –0.4 to 1.7; P = .20) and no funnel plot asymmetry was observed (Supplementary Figure 1), indicating no evidence of publication bias.

Methodologic Quality of Included Studies

Supplementary Table 7 presents an overview of the methodologic quality of included RCTs. The majority of trials mentioned the method used for randomization (93%) and adequate concealment of allocation (72%). Seventy percent of studies applied a double-blind design, 23% had a single-blind design, and 7% followed an open-label design. An independent blinded committee identified all suspected outcome events in each study. Ninety-three percent of studies used an intention-to-treat analysis at least for the safety analysis. The number of patients lost to follow-up evaluation varied between 0.1% and 2.5%, but were reported in only 53% of studies.

Gastrointestinal Bleeding

Nineteen trials (44%) reported separate data on GIB. Two small trials yielded null events in both groups and therefore were excluded from the GIB analyses.[35,38] A total of 1101 GIB events in 75,081 patients were reported (1.5%) (Supplementary Table 8). These GIBs were predominantly major bleeds (89%). The percentage of GI bleeds per trial in the nOAC group was low in the trials on OS (nOAC, 0.1%; control, 0.2%), intermediate in the trials on AF (nOAC, 2.1%; control, 1.6%) and DVT/PE (nOAC, 3.0%; control, 1.9%), and high in the trials on ACS (nOAC, 5.3%; control, 1.0%). The NNH was 500 (95% CI, -10,000 to 200), meaning that if 1000 patients were treated with the nOAC instead of standard care, this would result in 2 additional GIBs.

Four of 17 studies showed an increased risk, 12 a comparable risk, and 1 a lower risk of GIB when the nOAC was administered compared with the standard care. After pooling the results of 17 RCTs, the nOAC were found to be associated with a higher risk of GIB compared with standard care (pooled OR, 1.45; 95% CI, 1.07–1.97), but with substantial heterogeneity (I2, 61%). First, a considerable part of the increased risk could be attributed to the 2 trials on ACS (pooled OR, 5.21; 95% CI, 2.58–10.53; I2, 0%). To illustrate, the NNH was 24 (95% CI, 17–42), meaning that per 24 patients treated with the nOAC on top of standard care for ACS, 1 extra GIB would occur. Second, the risk of GIB with nOAC was increased for the 2 trials on DVT/PE (pooled OR, 1.59; 95% CI, 1.03–2.44; I2 27%), but not for other indications for nOAC. The calculated OR (95% CI) of each trial is shown in Figure 2A and 2B. With post hoc meta-regression, we studied the effect of indication of use (therapeutic use of nOAC vs prophylactic use). This showed no difference between therapeutic or prophylactic use when adjusted for comparator (placebo vs antithrombotic agent).

Forrest plot of GIB with subgroup analysis by indication. (B) Forrest plot of GIB with subgroup analysis by drug. Data are presented as OR (95% CI) using a random-effects model and I2 test for heterogeneity. Api, apixaban; bet, betrixaban; dab, dabigatran; edo, edoxaban; riv, rivaroxaban; ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.

In a subgroup analysis of individual drugs, dabigatran (3 studies;[9,57,64] I2, 36%), and rivaroxaban (5 studies;[10,33,39,41,58] I2, 0%) were associated with a significant increase in risk of GIB, whereas apixaban (8 studies; I2, 0%) and edoxaban (1 study[27]) were not. The pooled OR of GIB associated with dabigatran use was 1.58 (95% CI, 1.29–1.93) (Figure 2B). Expressed in terms of NNH: per 83 patients treated with dabigatran compared with standard care, 1 additional GIB would occur (95% CI, 59–143). The GIB risk associated with use of rivaroxaban had an OR of 1.48 (95% CI, 1.21–1.82). When adjusting for indication of use (therapeutic vs prophylactic), the risk of rivaroxaban remained significantly higher than that of apixaban (OR, 1.77; 95% CI, 1.32–2.38). Analysis by comparator, adjusted for indication of use, revealed no significant differences between different comparators.

In the sensitivity analysis, we excluded studies that compared nOAC with placebo therapy. No major deviations were seen, except for the risk of GIB during DVT/PE treatment, which reduced and became inconclusive (OR, 1.53; 95% CI, 0.99–2.36). Complete results of this sensitivity analysis are shown in Supplementary Table 8.

Clinically Relevant Bleeding

Because GIB is a substantial component of clinically relevant bleeding, we also included this in our analysis. All 43 trials reported on clinically relevant bleeding. The overall risk of clinically relevant bleeding was significantly higher with the use of nOAC compared with standard care (OR, 1.16; 95% CI, 1.00–1.34). Considerable overall heterogeneity, however, was observed (I2, 83%).

In a subgroup analysis in which different indications for nOAC therapy were considered, we found that patients treated for ACS have an increased risk of bleeding (OR, 2.06; I2, 22%) in contrast to patients receiving thromboprophylaxis during OS (OR, 1.05; I2, 36%). The other indications did not show a significantly increased risk, but this may be hampered by the substantial heterogeneity. Subgroup analysis by individual drug showed a slightly increased risk of rivaroxaban compared with standard care (OR, 1.31; 95% CI, 1.04–1.64), but likewise was marked by heterogeneity (I2, 85%), limiting a solid conclusion on the risk of clinically relevant bleeding (Figure 3 and Supplementary Table 8). The risk of clinically relevant bleeding did not differ by drug when adjusted for indication of use.

Forrest plot of clinically relevant bleeding summarized by indication and by drug. Data are presented as OR (95% CI) using a random effects model and an I2 test for heterogeneity. ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.

In the sensitivity analysis, excluding studies comparing with placebo, the overall clinically relevant bleeding risk was not increased (OR, 0.98; 95% CI, 0.88–1.10; I2, 65%) .


This systematic review and meta-analysis on 43 trials shows that the nOACs are associated with a modest, but significantly higher, risk of GIB compared with current standard care. This risk is the highest in patients treated for thrombosis (ACS and DVT/PE). In ACS, nOACs were administered on top of other antithrombotic medication, increasing the well-known cumulative risk of GIB.[5] The risk of GIB in patients treated for DVT/PE or receiving thromboprophylaxis for AF is higher than in patients receiving thromboprophylaxis after OS, this might suggest a dose and/or duration effect on top of difference in risk caused by patient characteristics in the different indication groups. However, within the subgroup of AF patients, only patients treated with dabigatran and rivaroxaban carry a higher GIB risk, but not with apixaban. Because head-to-head studies between nOAC in AF have not been performed, it is not possible to determine the drugs with the lowest GIB risk in AF without applying statistically indirect comparisons. A network meta-analysis on overall safety was conducted by others on OS patients and showed no significant differences.[65]

The major strength of this meta-analysis was its focus on GIB. We provide a complete review of 43 trials with a total of 151,578 patients. Given the implementation of nOAC on a large scale, all currently available types of nOAC and all present indications were included because GI physicians will have to deal with GIB complications, irrespective of drug or indication. The data conveyed are corroborated by 2 small meta-analyses with GIB as a secondary safety outcome and in which in total only 3 studies for AF were reviewed. [66,67] For optimal clinical relevance, we included only data obtained with the indication-specific registered/recommended dose per drug, instead of combining all levels of dosages per trial, which was performed in meta-analyses assessing overall risk/benefit of thromboprophylaxis after OS.[8,65]

Two limitations of the current study need to be addressed: (1) study design and GIB report of included studies, and (2) heterogeneity between studies. First, all included studies have been designed for showing noninferior or superior efficacy of nOAC vs current standard care. As a consequence, GIB is not reported as a safety outcome in the majority of studies and will have to be assessed by future studies or by a critical assessment of published studies. A large number of included studies reported only on the composite end point of bleeding outcomes in general. Although the use of this end point has the advantage of increased power, a difference in GIB risk therefore cannot be investigated. However, when studies separately reported on GIB, this was performed for major bleedings, but mostly not for clinically relevant nonmajor bleedings. This led to an underestimation of the risk of all clinically relevant GIBs (ie, composed of both major and clinically relevant nonmajor GIBs). In addition, for GIB there was no standard definition according to a scientific commission, but most trials reported used a uniform definition to identify GIB. Regarding heterogeneity, which is inevitable with current available data, we applied a random-effects model and excluded observational cohorts, healthy volunteer studies, nonregistered drugs, and unpublished data. Furthermore, we addressed all perceived sources of heterogeneity by prespecified subgroup analysis and meta-regression by indication, type of nOAC, and comparator. Analysis by concomitant use of antiplatelet therapy was not feasible owing to lack of stratification of outcome by use of antiplatelet therapy.

Some statistical issues merit clarification. First, we calculated risk estimates per study by means of ORs. Although it would have been preferable to calculate hazard ratios, the rationale to compute ORs was that the mean follow-up time until GIB was not reported per treatment arm for any study. The OR can be interpreted as an estimate of the relative risk because the overall occurrence of GIB is rare (1.5%). Second, for the analysis on GIB, following standard practice, we excluded 2 studies that had no events in both arms. This exclusion was performed because such studies do not provide any indication of either the direction or magnitude of the relative treatment effect, whereas exclusion of the 2 trials would not affect the point estimate. Both studies were of relatively small size (and thus would have had a low weight in the meta-analyses, together equaling approximately 2%).

As evidence of the superior efficacy of nOAC accumulates,[8,65,67] it is important to consider 2 crucial issues. First, most trials used extensive exclusion criteria to enroll only those patients with a presumed low risk of GIB complications attributable to anticoagulants. It is estimated that when these drugs are marketed for daily clinical practice, almost 25%–40% of future users are high-risk patients and the risk of hemorrhage can be as much as 3- to 15-fold increased.[68] It is tempting to speculate that the balance between efficacy and safety will shift unfavorably in these patients because the bleeding risk increases to a much greater extent than the risk of thromboembolism. Second, data on concomitant proton pump inhibitor (PPI) use was not available, except for one trial.[62] A recent consensus guideline states that PPIs should be considered in any person with a risk factor for GIB receiving any type of antithrombotic agent[69] because PPIs have proven to reduce the risk of upper GIB among both traditional NSAID users, low-dose aspirin users, and among patients taking clopidogrel.[70] Future trials, investigating whether gastroprotective agents could increase NNH in patients on nOAC, are warranted. This is of importance because many patients may use nOAC for a considerable duration of time and mostly have significant comorbidity.

In conclusion, we have shown that the gastrointestinal bleeding risk associated with nOAC use might be higher compared with standard care. The current evidence, however, is based on a highly selected patient group with a low bleeding risk, disallowing a true reflection of future patients in daily clinical practice. We recommend that future studies specifically report on the gastrointestinal bleeding risk to further elucidate the true incidence and associated risk. Subsequently, co-administration of gastroprotective agents could be beneficial and warrants further investigations.




Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy.


Objective To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide.

Design Systematic review and meta-analysis.

Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings.

Study selection Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy.

Results 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I2=29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I2= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I2=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I2=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I2=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin.

Conclusions Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed.


Source: BMJ



Perceived job insecurity as a risk factor for incident coronary heart disease: systematic review and meta-analysis.


Objective To determine the association between self reported job insecurity and incident coronary heart disease.

Design A meta-analysis combining individual level data from a collaborative consortium and published studies identified by a systematic review.

Data sources We obtained individual level data from 13 cohort studies participating in the Individual-Participant-Data Meta-analysis in Working Populations Consortium. Four published prospective cohort studies were identified by searches of Medline (to August 2012) and Embase databases (to October 2012), supplemented by manual searches.

Review methods Prospective cohort studies that reported risk estimates for clinically verified incident coronary heart disease by the level of self reported job insecurity. Two independent reviewers extracted published data. Summary estimates of association were obtained using random effects models.

Results The literature search yielded four cohort studies. Together with 13 cohort studies with individual participant data, the meta-analysis comprised up to 174 438 participants with a mean follow-up of 9.7 years and 1892 incident cases of coronary heart disease. Age adjusted relative risk of high versus low job insecurity was 1.32 (95% confidence interval 1.09 to 1.59). The relative risk of job insecurity adjusted for sociodemographic and risk factors was 1.19 (1.00 to 1.42). There was no evidence of significant differences in this association by sex, age (<50 v ≥50 years), national unemployment rate, welfare regime, or job insecurity measure.

Conclusions The modest association between perceived job insecurity and incident coronary heart disease is partly attributable to poorer socioeconomic circumstances and less favourable risk factor profiles among people with job insecurity.

Source: BMJ

Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis.


Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease.
METHODS: We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model.
FINDINGS: Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0.78, 95% CI 0.61-0.98).
INTERPRETATION: Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder.


Comments from Clinical Raters


Novel and potentially practice-changing. We currently use calcium-based phosphate binders to control lab abnormalities, usually switching to sevalamer when hypercalcaemia becomes an issue. This review shows that the mortality in RCTs is higher in people treated with calcium binders rather than sevalamer. Whether sevalamer is protective or calcium binders harmful is not addressed by this work, and there are no data to answer this important question. The cost of sevalamer compared with calcium is another important issue. We also do not know whether the harms associated with calcium could be mitigated by a different strategy with the calcium concentration in the dialysate. Finally, this meta-analysis has substantial heterogeneity, only 70 events separating the groups, and borderline statistical significance. Is this good enough evidence on which to change practice?


Although previous meta-analyses suggested similar results favouring non-calcium-containing phosphate binders on patient survival, this update appears to confirm it. It, therefore, has a stronger message about the need for changing clinical practice about first-choice phosphate binders. I do not necessarily agree with the phrasing in the conclusion about harm of calcium-containing phosphate binders per se, since many patients do not always like or tolerate the first-choice binder and could end up requiring a calcium-containing binder that nevertheless is probably better than not taking any binding at all. A good quality meta-analysis.

Source: Lancet


Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.

Ovarian cancer is the eighth most common cancer in women and it is usually diagnosed at an advanced stage. The majority of ovarian tumours are epithelial in origin. Women with relapsed epithelial ovarian cancer (EOC) often have a reduced performance status with a limited life expectancy, therefore maintaining quality of life with effective symptom control is the main purpose of treatment. Drug treatment of relapsed disease is directed by the platinum-free interval: relapsed platinum-sensitive disease is usually re-treated with platinum-based therapy and platinum-resistant disease challenged with non-platinum drugs. However, the side-effects of chemotherapy agents may be severe and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride is one of several treatment modalities that may be considered for single-agent treatment of relapsed EOC, or used in combination with other drugs. 

OBJECTIVES: To assess the efficacy and safety of PLD in women with relapsed epithelial ovarian cancer (EOC). SEARCH
METHODS: We searched the Cochrane Gynaecological Cancer Group (CGCG) trials register, CENTRAL, MEDLINE and EMBASE from 1990 to February 2013. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.
SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer.
DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses using RevMan 5.2 software.
MAIN RESULTS: We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC. Overall survival (OS) was similar for these treatments, however progression-free survival (PFS) was longer with PLD/carbo (1164 participants; hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.74 to 0.97; I(2) = 7%; P value 0.01). PLD/carbo was associated with significantly more anaemia and thrombocytopenia than PAC/carbo, whereas PAC/carbo was associated with significantly more alopecia, neuropathies, hypersensitivity reactions and arthralgias/myalgias. PLD/carbo was well-tolerated and women receiving this treatment were significantly less likely to discontinue treatment than those receiving PAC/carbo (two studies, 1150 participants; risk ratio (RR) 0.38, 95% CI 0.26 to 0.57; I(2) = 0%; P < 0.00001).Five studies compared other agents to PLD alone. None of these agents were associated with significantly better survival or severe adverse-event profiles than PLD. Topotecan and gemcitabine were associated with significantly more haematological severe adverse events than PLD, and patupilone was associated with significantly more severe neuropathies and diarrhoea. Severe hand-foot syndrome (HFS) occurred consistently more frequently with PLD than the other drugs.Three studies compared PLD combination treatment to PLD alone. Two combinations resulted in a significantly longer PFS compared with PLD alone: trabectedin (TBD)/PLD (one study, 672 women; HR 0.79, 95% CI 0.65 to 0.96; P value 0.02) and vintafolide (EC145)/PLD (one study, 149 women; HR 0.63, 95% CI 0.41 to 0.97; P value 0.04). TBD/PLD appeared to benefit the partially platinum-sensitive subgroup only. Further studies are likely to have an important impact on our confidence in these estimates. TBD/PLD was associated with significantly more haematological and gastrointestinal severe adverse events than PLD alone, whereas EC145/PLD appeared to be well-tolerated.For platinum-resistant relapsed EOC, the median PFS and OS for single-agent PLD across seven included studies was 15 weeks and 54 weeks, respectively. Severe HFS occurred significantly more frequently in women receiving a 50 mg/m(2) dose of PLD than those receiving less than 50 mg/m(2) (17% versus 2%, respectively; P value 0.01).
AUTHORS’ CONCLUSIONS: In platinum-sensitive relapsed epithelial ovarian cancer, PLD/carbo is more effective than PAC/carbo and is better tolerated; PLD/carbo should therefore be considered as first-line treatment in women with platinum-sensitive relapsed EOC. PLD alone is a useful agent for platinum-resistant relapsed EOC, however it remains unclear how it compares with other single agents for this subgroup and in what order these agents should be used. There is insufficient evidence to support the use of PLD in combination with other agents in platinum-resistant relapsed EOC.

Source: Cochrane Database