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Seminars in Perinatology Jun 2006Ibuprofen, a nonsteroidal antiinflammatory drug, widely used as antipyretic, antiinflammatory, and analgesic agent and for therapy of arthritis, exerts a dose-dependent... (Comparative Study)
Comparative Study Review
Ibuprofen, a nonsteroidal antiinflammatory drug, widely used as antipyretic, antiinflammatory, and analgesic agent and for therapy of arthritis, exerts a dose-dependent constriction of the ductus arteriosus in newborn lambs. Two intravenous preparations, namely ibuprofen lysine and ibuprofen-THAM, have been studied in preterm newborns with patent ductus arteriosus. Clinical trials have compared IV ibuprofen to placebo, or to indomethacin. Pharmacodynamic effects of this drug before and after its administration have also been evaluated. Compared with placebo, IV ibuprofen effectively closed PDA with minimal effect on renal function. One study using intravenous ibuprofen-THAM showed decreased renal function and increased risk of NEC and PPHN. Compared with indomethacin, IV ibuprofen lysine exerted similar efficacy (75% to 93% closure). However, indomethacin increased abnormal renal function and decreased mesenteric and cerebral blood flow and bio-energetics. Two clinical trials showed that ibuprofen did not reduce the incidence of intraventricular hemorrhage compared with placebo. The drug has prolonged elimination (plasma half-life = ca 23 hours), suggesting that once daily dosing is appropriate. Dose finding studies indicate that a starting dose of 10 mg/kg followed by 5 mg/kg/d for 2 more days provides optimal efficacy with the least adverse effects. Neonatal data on ibuprofen and indomethacin indicate that, on the first day of life when IVH prevention is desired, indomethacin and not ibuprofen should be used since ibuprofen has no effect on IVH risk. On or after the second day of postnatal life, when early or therapeutic PDA closure is needed, ibuprofen and not indomethacin is probably the first choice due to its better adverse event profile.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Ductus Arteriosus, Patent; Female; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intravenous; Male; Randomized Controlled Trials as Topic
PubMed: 16813969
DOI: 10.1053/j.semperi.2006.04.003 -
The Cochrane Database of Systematic... Apr 2018In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically; or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. An association between prenatal or postnatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported.
OBJECTIVES
To determine the effectiveness and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for treatment of an echocardiographically diagnosed PDA in preterm or low birth weight infants.
SEARCH METHODS
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 6 November 2017), Embase (1980 to 6 November 2017), and CINAHL (1982 to 6 November 2017). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials.
SELECTION CRITERIA
We included RCTs in which paracetamol was compared to no intervention, placebo or other agents used for closure of PDA irrespective of dose, duration and mode of administration in preterm (≤ 34 weeks' postmenstrual age) infants. We both reviewed the search results and made a final selection of potentially eligible articles by discussion. We included studies of both prophylactic and therapeutic use of paracetamol.
DATA COLLECTION AND ANALYSIS
We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for the following outcomes when data were available: failure of ductal closure after the first course of treatment; neurodevelopmental impairment; all-cause mortality during initial hospital stay (death); gastrointestinal bleed or stools positive for occult blood; and serum levels of creatinine after treatment (µmol/L).
MAIN RESULTS
We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) -0.02, 95% CI -0.09 to 0.09); I² = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD -0.06, 95% CI -0.09 to -0.02); I² = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence).Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD -0.21 (95% CI -0.41 to -0.02); I² = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence).Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I² = 11%; typical RD -0.01, 95% CI -0.09 to 0.08; I² = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group.
AUTHORS' CONCLUSIONS
Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made.
Topics: Acetaminophen; Administration, Oral; Ductus Arteriosus, Patent; Humans; Ibuprofen; Indomethacin; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Injections, Intravenous; Oxygen Inhalation Therapy; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 29624206
DOI: 10.1002/14651858.CD010061.pub3 -
The Cochrane Database of Systematic... Mar 2015In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. Concerns have been raised that in neonatal mice paracetamol may cause adverse effects on the developing brain, and an association between prenatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported.
OBJECTIVES
To determine the efficacy and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for closure of a PDA in preterm or low-birth-weight infants.
SEARCH METHODS
We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, EMBASE and CINAHL. We searched abstracts from the meetings of the Pediatric Academic Societies and the Perinatal Society of Australia and New Zealand. We searched clinicaltrials.gov; controlled-trials.com; anzctr.org.au; World Health Organization International Clinical Trials Registry Platform at who.int/ictrp for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google Scholar(TM) to identify grey literature. All searches were conducted in December 2013. A repeat search of MEDLINE in August 2014 did not identify any new trials.
SELECTION CRITERIA
We identified two randomised controlled trials (RCTs) that compared oral paracetamol to oral ibuprofen for the treatment of an echocardiographically diagnosed PDA in infants born preterm (≤ 34 weeks postmenstrual age (PMA)).
DATA COLLECTION AND ANALYSIS
We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group.
MAIN RESULTS
Two unmasked studies of treatment of PDA that enrolled 250 infants were included. The sequence of randomisation and the allocation to treatment groups were concealed in both studies. In one study the cardiologist assessing PDA closure was blinded to group allocation of the infant. In the other study it was not stated if that was the case or not. The quality of the trials, using GRADE, was low for the primary outcome of PDA closure and moderate for all other important outcomes. There was no significant difference between treatment with oral paracetamol versus oral ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.90, 95% confidence interval (CI) 0.67 to 1.22; typical risk difference (RD) -0.04, 95% CI -0.16 to 0.08; I(2) = 0 % for RR and 23% for RD).There were no significant differences between the paracetamol and the ibuprofen groups in the secondary outcomes except for 'duration for need of supplemental oxygen' (mean difference -12 days, 95% CI -23 days to -2 days; 1 study, n = 90) and for hyperbilirubinaemia (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, 95% CI -0.29 to -0.01; number needed to treat to benefit (NNTB) 7, 95% CI 3 to 100 in favour of paracetamol; 1 study, n = 160).
AUTHORS' CONCLUSIONS
Although a limited number of infants with a PDA have been studied in randomised trials of low to moderate quality according to GRADE, oral paracetamol appears to be as effective in closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse effects on the developing brain from paracetamol, and another report of an association between prenatal paracetamol and the development of autism or autism spectrum disorder in childhood, long-term follow-up to at least 18 to 24 months postnatal age must be incorporated in any studies of paracetamol in the newborn population. Such trials are required before any recommendations for the use of paracetamol in the newborn population can be made.
Topics: Acetaminophen; Administration, Oral; Ductus Arteriosus, Patent; Humans; Ibuprofen; Indomethacin; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Oxygen Inhalation Therapy; Randomized Controlled Trials as Topic
PubMed: 25758061
DOI: 10.1002/14651858.CD010061.pub2 -
Microsurgery Nov 2016Reconstruction of the distal radius in children is cumbersome, requiring simultaneous restoration of joint function and axial growth. Vascularized proximal fibular... (Review)
Review
PURPOSE
Reconstruction of the distal radius in children is cumbersome, requiring simultaneous restoration of joint function and axial growth. Vascularized proximal fibular epiphyseal transfers (VFET) have been popularized over non-vascularized transfers and prosthesis. This systematic review aims to evaluate the effectiveness of VFET and its associated complications.
METHODS
Electronic database of PubMed MEDLINE was searched between 1970 and 2014. Studies reporting VFET for distal radius reconstruction in children (<15 years old) with clear reporting of technique (vascular pedicle) and objective outcome measures were included. Outcomes of interest were rate of graft growth, bone union and complications. A one-way Analysis of Variance (ANOVA) test was used to compare growth rates between pedicle types.
RESULTS
Fourteen studies met the inclusion criteria, representing 25 patients. Pedicles used were anterior tibial (44%), peroneal (16%), or bi-pedicled (40%) anastomosed in antegrade (64%) or reverse flow (36%) fashion. Among all pedicle types, best results were achieved using anterior tibial artery with reversed flow, yielding average growth rate of 0.83 cm/year (P = 0.01). Recipient complications included four premature epiphyseal plate closures, a flap loss, and six wrist radial deviations. Donor complications included six common peroneal nerve palsies (five temporary, a permanent), and a talocalcaneal instability. Overall complication rates between pedicle types were comparable (P = 0.062).
CONCLUSION
VFET may be a surgical option capable of restoring joint function and axial growth potential in select patients. The reverse flow technique based on the anterior tibial artery may result in superior outcomes. However, the overall complication rate is high and permanent peroneal nerve palsy may result.
LEVEL OF EVIDENCE
IV © 2015 Wiley Periodicals, Inc. Microsurgery 36:705-711, 2016.
Topics: Bone Transplantation; Child; Epiphyses; Fibula; Free Tissue Flaps; Humans; Postoperative Complications; Radius; Plastic Surgery Procedures
PubMed: 26497641
DOI: 10.1002/micr.22521 -
Journal of Perinatology : Official... Dec 2022To examine the efficacy of dual medication therapy (intervention) (DMT: acetaminophen and ibuprofen) vs. single medication therapy (control) (SMT: ibuprofen) for medical... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To examine the efficacy of dual medication therapy (intervention) (DMT: acetaminophen and ibuprofen) vs. single medication therapy (control) (SMT: ibuprofen) for medical management of PDA (outcomes) in preterm infants (population).
STUDY DESIGN
We systematically searched multiple sources to identify randomized controlled trials (RCT) and non-randomized studies (NRS) that compared DMT to SMT for management of hemodynamically significant PDA.
RESULTS
We identified two RCTs and four NRS. There were no differences in the rates of successful PDA closure following the first treatment course between DMT and SMT (RR = 1.23 [95% CI 0.89-1.70] for NRS and RR = 1.18 [95% CI 0.66-2.10] for RCTs), nor were there significant differences in secondary outcomes and adverse events including PDA ligation, bronchopulmonary dysplasia, and necrotizing enterocolitis etc. Markers of hepatic/renal function did not change significantly during treatment.
CONCLUSION
We found no evidence for superiority of DMT over SMT in PDA management.
Topics: Infant, Newborn; Humans; Ductus Arteriosus, Patent; Ibuprofen; Acetaminophen; Indomethacin; Infant, Low Birth Weight; Infant, Premature
PubMed: 36008521
DOI: 10.1038/s41372-022-01500-8 -
Neonatology 2012Pharmacological closure of patent ductus arteriosus (PDA) is commonly achieved by intravenous (IV) administration of ibuprofen or indomethacin. Occasionally, oral... (Meta-Analysis)
Meta-Analysis Review
Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis.
BACKGROUND
Pharmacological closure of patent ductus arteriosus (PDA) is commonly achieved by intravenous (IV) administration of ibuprofen or indomethacin. Occasionally, oral ibuprofen is used for PDA treatment although its efficacy and safety are unclear.
OBJECTIVES
To systematically review randomized and quasi-randomized trials comparing oral ibuprofen with IV ibuprofen or IV indomethacin for closure of PDA in preterm infants.
METHODS
The standard search methods of the Cochrane Neonatal Review Group were used.
RESULTS
We identified two studies (n = 166) of good methodological quality comparing oral ibuprofen with IV ibuprofen and three small trials (n = 92) of moderate methodological quality comparing oral ibuprofen to IV indomethacin. Meta-analysis showed higher PDA closure rate of oral ibuprofen versus IV ibuprofen but no difference between oral ibuprofen and IV indomethacin. Meta-analysis did not indicate a significant difference in adverse effects.
CONCLUSION
Oral ibuprofen for PDA closure appears to be as effective as IV ibuprofen and IV indomethacin. Due to small sample size, lack of data in extremely preterm neonates, and methodological limitations of reviewed trials, definitive conclusions cannot be drawn. Randomized trials with a low risk of bias and adequate sample size in extremely preterm infants are urgently needed.
Topics: Administration, Oral; Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Infant, Premature; Infusions, Intravenous; Randomized Controlled Trials as Topic
PubMed: 22414850
DOI: 10.1159/000335332 -
The Cochrane Database of Systematic... Jul 2010Persistent patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Prostaglandin synthetase inhibitors such as indomethacin promote... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Persistent patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Prostaglandin synthetase inhibitors such as indomethacin promote PDA closure but also have potential side effects. The effect of the prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA would be exposed to indomethacin, warrants particular scrutiny.
OBJECTIVES
To determine the effect of prophylactic indomethacin on mortality and morbidity in preterm infants.
SEARCH STRATEGY
The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 5, 2010), MEDLINE, EMBASE and CINAHL (until April 2010), conference proceedings, and previous reviews.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials that compared prophylactic indomethacin versus placebo or no drug in preterm infants.
DATA COLLECTION AND ANALYSIS
The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two review authors.
MAIN RESULTS
Nineteen eligible trials in which 2872 infants participated were identified. Most participants were very low birth weight, but the largest single trial restricted participation to extremely low birth weight infants (N = 1202). The trials were generally of good quality.The incidence of symptomatic PDA [typical relative risk (RR) 0.44, 95% confidence interval (CI) 0.38 to 0.50] and PDA surgical ligation (typical RR 0.51, 95% CI 0.37,0.71) was significantly lower in treated infants. Prophylactic indomethacin also significantly reduced the incidence of severe intraventricular haemorrhage (typical RR 0.66, 95% CI 0.53 to 0.82). Meta-analyses found no evidence of an effect on mortality (typical RR 0.96, 95% CI 0.81 to 1.12) or on a composite of death or severe neurodevelopmental disability assessed at 18 to 36 months old (typical RR 1.02, 95% CI 0.90, 1.15).
AUTHORS' CONCLUSIONS
Prophylactic indomethacin has short-term benefits for preterm infants including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.
Topics: Cardiovascular Agents; Cerebral Hemorrhage; Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Intravenous; Randomized Controlled Trials as Topic
PubMed: 20614421
DOI: 10.1002/14651858.CD000174.pub2 -
Journal of Comparative Effectiveness... May 2021To systematically review ibuprofen, including versus indomethacin and paracetamol/acetaminophen, for the closure of patent ductus arteriosus (PDA). Pubmed, Embase,...
To systematically review ibuprofen, including versus indomethacin and paracetamol/acetaminophen, for the closure of patent ductus arteriosus (PDA). Pubmed, Embase, Cochrane and gray literature were searched to summarize ibuprofen outcomes in closure of PDA in published meta-analyses (MAs). Seven MAs were included. Including high dose (HD) use, ibuprofen is equivalent/superior to indomethacin, and inferior/equivalent to paracetamol. Oral ibuprofen had higher efficacy than IV ibuprofen, including compared with indomethacin and paracetamol. Ibuprofen had safety advantages over indomethacin. Indomethacin and paracetamol had safety advantages over IV ibuprofen. HD of ibuprofen increases efficacy, but not toxicity. Evidence on ibuprofen effectiveness and safety, including the dosage forms, is limited by heterogeneity in doses and the levels of methods quality and risk of bias.
Topics: Ductus Arteriosus, Patent; Humans; Ibuprofen; Indomethacin; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Meta-Analysis as Topic
PubMed: 33880942
DOI: 10.2217/cer-2020-0235 -
The Cochrane Database of Systematic... Feb 2012Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in Western countries. Standard treatment includes... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in Western countries. Standard treatment includes mono- or poly-chemotherapies. Nowadays, monoclonal antibodies are added, especially alemtuzumab and rituximab. However, the impact of these agents remains unclear, as there are hints of an increased risk of severe infections.
OBJECTIVES
To assess alemtuzumab compared with no further therapy, or with other anti-leukaemic therapy in patients with CLL.
SEARCH METHODS
We searched CENTRAL and MEDLINE (from January 1985 to November 2011), and EMBASE (from 1990 to 2009) as well as conference proceedings for randomised controlled trials (RCTs). Two review authors (KB, NS) independently screened search results.
SELECTION CRITERIA
We included RCTs comparing alemtuzumab with no further therapy or comparing alemtuzumab with anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with histologically-confirmed B-cell CLL. Both pretreated and chemotherapy-naive patients were included.
DATA COLLECTION AND ANALYSIS
We used hazard ratios (HR) as an effect measure for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for response rates, treatment-related mortality (TRM) and adverse events. Two review authors independently extracted data and assessed the quality of trials.
MAIN RESULTS
Our search strategies led to 1542 potentially relevant references. Of these, we included five RCTs involving 845 patients. Overall, we judged the quality of the five trials as moderate. All trials were reported as randomised and open-label studies. However, two trials were published as abstracts only, therefore, we were unable to assess the potential risk of bias for these trials in detail. Because of the small number of studies in each analysis (two), the quantification of heterogeneity was not reliable.Two trials (N = 356) assessed the efficacy of alemtuzumab compared with no further therapy. One trial (N = 335), reported a statistically significant OS advantage for all patients receiving alemtuzumab (HR 0.65 (95% confidence interval (CI) 0.45 to 0.94; P = 0.021). However, no improvement was seen for the subgroup of patients in Rai stage I or II (HR 1.07; 95% CI 0.62 to 1.84; P = 0.82). In both trials, the complete response rate (CRR) (RR 2.61; 95% CI 1.26 to 5.42; P = 0.01) and PFS (HR 0.58; 95% CI 0.44 to 0.76; P < 0.0001) were statistically significantly increased under therapy with alemtuzumab. The potential heterogeneity seen in the forest plot could be due to the different study designs: One trial evaluated alemtuzumab additional to fludarabine as relapse therapy; the other trial examined alemtuzumab compared with no further therapy for consolidation after first remission.There was no statistically significant difference for TRM between both arms (RR 0.57; 95% CI 0.17 to 1.90; P = 0.36). A statistically significant higher rate of CMV reactivation (RR 10.52; 95% CI 1.42 to 77.68; P = 0.02) and infections (RR 1.32; 95% CI 1.01 to 1.74; P = 0.04) occurred in patients receiving alemtuzumab. Seven severe infections (64%) in the alemtuzumab arm in the GCLLSG CLL4B study led to premature closure.Two trials (N = 177), evaluated alemtuzumab versus rituximab. Neither study reported OS or PFS. We could not detect a statistically significant difference for CRR (RR 0.85; 95% CI 0.67 to 1.08; P = 0.18) or TRM (RR 3.20; 95% CI 0.66 to 15.50; P = 0.15) between both arms. However, the CLL2007FMP trial was stopped early due to an increase in mortality in the alemtuzumab arm. More serious adverse events occurred in this arm (43% versus 22% (rituximab), P = 0.006).One trial (N = 297), assessed the efficacy of alemtuzumab compared with chemotherapy (chlorambucil). For this trial, no HR is reported for OS. Median survival has not yet been reached, 84% of patients were alive in each arm at the data cut-off or at the last follow-up date (24.6 months). The TRM between arms shows no statistical significant difference (0.6% versus 2.0%; P = 0.34). Alemtuzumab statistically significantly improves PFS (HR 0.58; 95% CI 0.43 to 0.77; P = 0.0001), time to next treatment (23.3 compared with 14.7 months; P = 0.0001), ORR (83.2% versus 55.4%; P < 0.0001), CRR (24.2% versus 2.0%; P < 0.0001), and minimal residual disease rate (7.4% versus 0%; P = 0.0008) compared with chlorambucil. Statistically, significantly more asymptomatic (51.7% versus 7.4%) and symptomatic cytomegalovirus (CMV) infections (15.4% versus 0%) occurred in the patients treated with alemtuzumab.
AUTHORS' CONCLUSIONS
In summary, the currently available evidence suggests an OS, CRR and PFS benefit for alemtuzumab compared with no further therapy, but an increased risk for infections in general, CMV infections and CMV reactivations. The role of alemtuzumab versus rituximab still remains unclear, further trials with longer follow-up and overall survival as primary endpoint are needed to evaluate the effects of both agents compared with each other. Alemtuzumab compared with chlorambucil seems to be favourable in terms of PFS, but a longer follow-up period and trials with overall survival as primary endpoint are needed to determine whether this effect will translate into a survival advantage.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Chlorambucil; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Randomized Controlled Trials as Topic; Rituximab; Vidarabine
PubMed: 22336834
DOI: 10.1002/14651858.CD008078.pub2 -
The Cochrane Database of Systematic... Jan 2008Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be... (Review)
Review
BACKGROUND
Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or treatment with indomethacin, has not been well established.
OBJECTIVES
To compare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA.
SEARCH STRATEGY
The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - July 2007), CINAHL (1982 - July 2007), EMBASE (1980 - July 2007); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002) or on line from May 2002 -July 2007. No language restrictions were applied.
SELECTION CRITERIA
All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA.
DATA COLLECTION AND ANALYSIS
Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data.
MAIN RESULTS
Only one study, trial B in the report of Gersony 1983, was found eligible. No additional studies were identified in the literature searches performed in July 2007. The trial compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity stage III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)].
AUTHORS' CONCLUSIONS
The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants. It should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care.
Topics: Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Ligation; Randomized Controlled Trials as Topic
PubMed: 18254035
DOI: 10.1002/14651858.CD003951.pub2