Number Needed To Treat To Benefit Research Articles

Safety of SGLT2 Inhibitors in Three Chronic Diseases.

This study aimed to assess the safety of SGLT2 inhibitors in type 2 diabetes, chronic kidney disease, and chronic heart failure considering the number needed to treat (NNT).Methods: Data were obtained from 10 morbidity-mortality trials and were pooled to calculate the NNTs. The number needed to treat to benefit (NNTB) is used to express beneficial outcomes, whereas the number needed to treat to be harmed (NNTH) is used for harmful outcomes. The eight safety outcomes of interest were fracture, diabetic ketoacidosis, amputation, urinary tract infection, genital infection, acute kidney injury, severe hypoglycemia, and volume depletion.A total of 10 trials involving 76319 patients were included in this meta-analysis. The mean follow-up was 2.35 years. SGLT2 inhibitors play a positive role in acute kidney injury and severe hypoglycemia, with the corresponding mean NNTBs being 157 and 561, respectively. SGLT2 inhibitors significantly increased the risk of diabetic ketoacidosis, genital infection, and volume depletion, with the corresponding mean NNTHs being 1014, 41, and 139. It was found that the safety of SGLT2 inhibitors was the same in three diseases and five SGLT2 inhibitors.SGLT2 inhibitors have a positive impact on acute kidney injury and severe hypoglycemia, but they increase the incidence of diabetic ketoacidosis, genital infection, and volume depletion.

Antiplatelet agents for the treatment of deep venous thrombosis.

Antiplatelet agents for the treatment of deep venous thrombosis.

21 Direct oral anticoagulants vs. vitamin K antagonists in the treatment of left ventricular thrombosis: a systematic review and meta-analysis

Abstract Aims Evidence about the use of direct oral anticoagulants (DOACs) in patients with left ventricular thrombosis (LVT) are emerging. The aim of our study was to provide a comprehensive synthesis of the available evidence concerning the clinical effects of DOACs vs. vitamin K antagonists (VKAs) in LVT treatment. Methods Systematic search of studies evaluating DOACs vs. VKAs use in patients with LVT was performed on 11 May 2021. Data were pooled by meta-analysis using a random-effects model. Odds ratios (OR) with relative 95% confidence intervals (CI) were used as measures of effect estimates. The primary efficacy and safety endpoint were ischaemic stroke and any bleeding, respectively. Secondary endpoints were LVT resolution, systemic embolism, major bleeding, haemorrhagic stroke, and all cause death. Results Twenty studies were included in the meta-analysis: 1391 patients were treated with DOACs and 1534 with VKAs. A significant reduction in the risk of ischaemic stroke [OR 0.67, 95% CI 0.45–0.98, P = 0.048, number needed to treat to benefit (NNTB) 22 (95% CI 15–43)] and any bleeding [OR 0.64, 95% CI 0.46–0.89, P = 0.009, NNTB 26 (95% CI 16–80)] was observed with DOACs compared to VKAs. No statistically significant difference was observed among the two treatment arms for the secondary endpoints. Conclusion Compared to VKAs, DOACs are associated with a reduced risk of ischaemic stroke and bleeding. In light of these findings, and the practical advantages of DOACs, additional large scale randomized controlled trials are needed to confirm the benefits of DOACs in patients with LVT.

Blood pressure targets in adults with hypertension.

This is the first update of this review first published in 2009. When treating elevated blood pressure, doctors usually try to achieve a blood pressure target. That target is the blood pressure value below which the optimal clinical benefit is supposedly obtained. "The lower the better" approach that guided the treatment of elevated blood pressure for many years was challenged during the last decade due to lack of evidence from randomised trials supporting that strategy. For that reason, the standard blood pressure target in clinical practice during the last years has been less than 140/90 mm Hg for the general population of patients with elevated blood pressure. However, new trials published in recent years have reintroduced the idea of trying to achieve lower blood pressure targets. Therefore, it is important to know whether the benefits outweigh harms when attempting to achieve targets lower than the standard target. The primary objective was to determine if lower blood pressure targets (any target less than or equal to 135/85 mm Hg) are associated with reduction in mortality and morbidity as compared with standard blood pressure targets (less than or equal to 140/ 90 mm Hg) for the treatment of patients with chronic arterial hypertension. The secondary objectives were: to determine if there is a change in mean achieved systolic blood pressure (SBP) and diastolic blood pressure (DBP associated with "lower targets" as compared with "standard targets" in patients with chronic arterial hypertension; and to determine if there is a change in withdrawals due to adverse events with "lower targets" as compared with "standard targets", in patients with elevated blood pressure. The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up toMay 2019: the Cochrane Hypertension Specialised Register, CENTRAL (2019, Issue 4), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. Randomised controlled trials (RCTs) comparing patients allocated to lower or to standard blood pressure targets (see above). Two review authors (JAA, VL) independently assessed the included trials and extracted data. Primary outcomes were total mortality; total serious adverse events; myocardial infarction, stroke, congestive heart failure, end stage renal disease, and other serious adverse events. Secondary outcomes were achieved mean SBP and DBP, withdrawals due to adverse effects, and mean number of antihypertensive drugs used. We assessed the risk of bias of each trial using the Cochrane risk of bias tool and the certainty of the evidence using the GRADE approach. MAIN RESULTS: This update includes 11 RCTs involving 38,688 participants with a mean follow-up of 3.7 years. This represents 7new RCTs compared with the original version. At baseline the mean weighted age was 63.1 years and the mean weighted blood pressure was 155/91 mm Hg. Lower targets do not reduce total mortality (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.05; 11 trials, 38,688 participants; high-certainty evidence) and do not reduce total serious adverse events (RR 1.04, 95% CI 0.99 to 1.08; 6 trials, 18,165 participants; moderate-certainty evidence). This means that the benefits of lower targets do not outweigh the harms as compared to standard blood pressure targets. Lower targets may reduce myocardial infarction (RR 0.84, 95% CI 0.73 to 0.96; 6 trials, 18,938 participants,absolute risk reduction (ARR) 0.4%, number needed to treat to benefit (NNTB) 250 over 3.7 years) and congestive heart failure (RR 0.75, 95% CI 0.60 to 0.92; 5 trials, 15,859 participants,ARR 0.6%, NNTB167 over 3.7 years) (low-certainty for both outcomes). Reduction in myocardial infarction and congestive heart failure was not reflected in total serious adverse events. This may be due to an increase in other serious adverse events (RR 1.44, 95% CI 1.32 to 1.59; 6 trials. 18,938 participants,absolute risk increase (ARI) 3%, number needed to treat to harm (NNTH) 33 over four years) (low-certainty evidence). Participants assigned to a "lower" target received one additional antihypertensive medication and achieved a significantly lower mean SBP (122.8 mm Hg versus 135.0 mm Hg,and a lower mean DBP (82.0 mm Hg versus 85.2 mm Hg,than those assigned to "standard target". For the general population of persons with elevated blood pressure, the benefits of trying to achieve a lower blood pressure target rather than a standard target (≤ 140/90 mm Hg) do not outweigh the harms associated with that intervention. Further research is needed to see if some groups of patients would benefit or be harmed by lower targets. The results of this review are primarily applicable to older people with moderate to high cardiovascular risk. They may not be applicable to other populations.

Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants. The standard search of the Cochrane Neonatal Review Group (CNRG) was performed in 2006 and updated in 2009. Updated search in September 2009 as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009. The searches were repeated in March 2012. The Pediatric Academic Societies' Annual meetings were searched electronically from 2000 to 2012 at Abstracts2ViewTM as were clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp). Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age. Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age). The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I2) test. No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I2 = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I2 = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported. The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.

Abstract 11: Assessing the True ImpACT-24B: Magnitude of Benefit of Sphenopalatine Ganglion Stimulation for Acute Ischemic Stroke with Confirmed Cortical Involvement

Background: Sphenopalatine ganglion (SPG) stimulation enhances collateral flow, stabilizes blood-brain barrier, and showed evidence of benefit in patients with confirmed cortical involvement (CCI) when started 8-24h after onset in the ImpACT-24B randomized trial. To characterize SPG stimulation benefit magnitude, we derived number needed to treat (NNT) values based on shifts over all levels of 3 month global disability. Methods: From the distribution of the 7-level modified Rankin Scale (mRS) at 3m in SPG- and sham-stimulation CCI patients, NNT to benefit (NNTB) and NNT to harm (NNTH) values were derived by automated (algorithmic min-max) and expert generation of joint outcome distribution tables. For dichotomized mRS outcomes, net NNT values were derived directly from absolute risk differences. Results: Among 520 patients with confirmed cortical infarction ineligible for thrombolysis, 244 were treated with SPG and 276 with sham stimulation. NNT values for dichotomized and shift mRS outcomes are shown in the Table. Of the 6 possible binary cutpoints on the mRS, 4 showed more favorable outcome with SPG stimulation. The dichotomized endpoint with the greatest group difference was ambulatory and capable of bodily self-care (mRS 0-3), 62.3% vs 51.1%, NNTB 8.9. Across all 6 individual possible dichotomizations of the mRS, the NNTB ranged from 8.9 to -166.7. For shifts by 1 or more levels across all 6 transitions of the mRS, the biologically most plausible NNTB was 5.7 (IQR 5.6-6.5), NNTH 34.5 (IQR 30.3-40.0), and net NNTB 6.8 (IQR 6.5-7.7), These values correlated closely with the automatically derived net NNTB of 5.9. Conclusions: The findings of this pivotal trial indicate that, out of every 1000 CCI patients treated with SPG stimulation, 146 patients will have a less disabled 3-month outcome, including 76 more who will be functionally independent. SPG stimulation can substantially improve the outcome of thrombolysis-ineligible acute ischemic stroke patients.

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

755: Nifedipine versus ritodrine during external cephalic version procedure: a case control study

Published series regarding interventions for facilitating external cephalic veriosn (ECV) have concluded that parenterally administered beta-stimulant tocolytics, increased ECV success rate and reduced the number of caesarean sections. However, there were insufficient data regarding calcium channel blockers (CCB) to provide good evidence regarding its efficacy. Given the paucity of literature, we aimed to compare the efficacy of nifedipine to that of ritodrine on ECV success rates. This is a retrospective case control study of prospectively collected data of patients who underwent ECV between January 2012 and December 2013 at Bikur Cholim Medical Center and Hadassah-Hebrew University Medical Center in Jerusalem, Israel. Patient undergoing ECV with tocolysis by ritordine were compared to those using nifedipine as tocolysis. Patients were matched in a one-to-one ration by parity and placental location. Overall, 148 women received ritodrine and 148 women received nifedipine prior to ECV procedure. Overall Success rate was higher among the ritodrine group (82.4% vs. 63.5%, p< 0.001). Among nuliiparous and among parous, success rate was higher in the ritodrine group (78.9% vs. 57.9% and 88.6% vs. 73.5%, p=0.001, p=0.04, respectively). Vaginal delivery rate was higher among the ritodrine group (86.5% vs. 68.9%, p< 0.001). Cesarean delivery rate was 31.1% for the nifedipine group versus 13.5% in the ritodrine group (p< 0.001). Number needed to treat to benefit (NNTb) 5.7 (95% confidence interval 3.7 to 12.1). Overall, 216/296 (72.9%) of ECV were successful. Ritodrine was associated with higher success rates as compared with nifedipine (56.5% vs. 32.5%, p< 0.001). In a multivariate analysis, ritodrine tocolytic therapy was independently associated higher ECV success rates as compared with nifedipine (OR 4.54, 95% CI 2.38-9.09. Higher AFI (OR 1.16, 95% CI 1.05-1.28) and nulliparity (OR 0.16, 95% CI 0.08-0.30) were additional independent predictors of ECV outcome. Ritordine significantly improve the success of ECV compared to nifedipine. Both drugs are shown to be safe.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA).

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane Review first published in 2010 and previously updated in 2014. To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) compared with non-surgical treatment in the management of children with PFAPA. The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2019, Issue 4); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 15 October 2019. Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA. We used the standard methodological procedures expected by Cochrane. The primary outcomes were the proportion of children whose symptoms have completely resolved and complications of surgery (haemorrhage and number of days of postoperative pain). Secondary outcomes were: number of episodes of fever and the associated symptoms; severity of episodes; use of corticosteroids; absence or time off school; quality of life. We used GRADE to assess the certainty of the evidence for each outcome. Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias. One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months. Combining the trial results suggests that patients with PFAPA likely experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution) (moderate-certainty evidence). Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Surgery probably results in a large overall reduction in the average number of episodes over the total length of follow-up (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years (moderate-certainty evidence). Surgery also likely reduces severity, as indicated by the length of PFAPA symptoms during these episodes. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group (moderate-certainty evidence). The evidence suggests that the proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92) (low-certainty evidence). Other outcomes such as absence from school and quality of life were not measured or reported. The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate certainty (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.

Nifedipine versus ritodrine during external cephalic version procedure: a case control study

Objective Published series regarding interventions for facilitating external cephalic version (ECV) have concluded that parenterally administered beta-stimulant tocolytics, increased ECV success rate and reduced the number of cesarean sections. However, there were insufficient data regarding calcium channel blockers to provide good evidence regarding its efficacy. Given the paucity of literature, we aimed to compare the efficacy of nifedipine to that of ritodrine on ECV success rates. Methods This is a retrospective case control study of prospectively collected data of patients who underwent ECV between January 2012 and December 2013 at Bikur Cholim Medical Center and Hadassah-Hebrew University Medical Center in Jerusalem, Israel. Patient undergoing ECV with tocolysis by ritodrine were compared with those using nifedipine as tocolysis. Patients were matched in a one-to-one ration by parity and placental location. Results Overall, 148 women received ritodrine and 148 women received nifedipine before ECV procedure. Overall success rate was higher among the ritodrine group (82.4 vs. 63.5%, p < .001). Among nulliparous and among parous, success rate was higher in the ritodrine group (78.9 vs. 57.9 and 88.6 vs. 73.5%, p = .001, p = .04, respectively). Vaginal delivery rate was higher among the ritodrine group (86.5 vs. 68.9%, p < .001). Cesarean delivery rate was 31.1% for the nifedipine group versus 13.5% in the ritodrine group (p < .001). Number needed to treat to benefit (NNTb) 5.7 (95% confidence interval 3.7–12.1). Overall, 216 of 296 (72.9%) of ECV were successful. Ritodrine was associated with higher success rates as compared with nifedipine (56.5 vs. 32.5%, p < .001). In a multivariate analysis, ritodrine tocolytic therapy was independently associated higher ECV success rates as compared to nifedipine (OR 4.54, 95% CI 2.38–9.09). Higher amniotic fluid index (OR 1.16, 95% CI 1.05–1.28) and nulliparity (OR 0.16, 95% CI 0.08–0.30) were additional independent predictors of ECV outcome. Conclusion Ritodrine significantly improve the success of ECV compared with nifedipine. Both drugs are shown to be safe.

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs.Primary objectivesTo determine the effectiveness and safety of ibuprofen compared to placebo/no intervention, or other cyclo-oxygenase inhibitor drugs in the prevention of PDA in preterm infants.We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10), MEDLINE via PubMed (1966 to 17 October 2018), Embase (1980 to 17 October 2018), and CINAHL; 1982 to 17 October 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.Randomised and quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm or low birth weight infants.We extracted outcomes data including presence of PDA on day three or four of life (after 72 hours of treatment), need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, cerebral, renal, pulmonary, and gastrointestinal complications. We performed meta-analyses and reported treatment estimates as typical mean difference (MD), risk ratio (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNTB) or to harm (NNTH), along with their 95% confidence intervals (CI). We assessed between-study heterogeneity by the I-squared test (I²). We used the GRADE approach to assess the quality of evidence.In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease.This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended.A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.

Band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices.

The presence of oesophageal varices is associated with the risk of upper gastrointestinal bleeding. Endoscopic variceal ligation is used to prevent this occurrence but the ligation procedure may be associated with complications. To assess the beneficial and harmful effects of band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices. We combined searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 9 February 2019. We included randomised clinical trials comparing band ligation verus no intervention regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. Included participants had cirrhosis and oesophageal varices with no previous history of variceal bleeding. Three review authors extracted data independently. The primary outcome measures were all-cause mortality, upper gastrointestinal bleeding, and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RRs) with 95% confidence intervals (CIs) and I2 values as a marker of heterogeneity. In addition, we calculated the number needed to treat to benefit (NNTTB) for the primary outcomes . We assessed bias control using the Cochrane Hepato-Biliary domains; determined the certainty of the evidence using GRADE; and conducted sensitivity analyses including Trial Sequential Analysis. Six randomised clinical trials involving 637 participants fulfilled our inclusion criteria. One of the trials included an additional small number of participants (< 10% of the total) with non-cirrhotic portal hypertension/portal vein block. We classified one trial as at low risk of bias for the outcome, mortality and high risk of bias for the remaining outcomes; the five remaining trials were at high risk of bias for all outcomes. We downgraded the evidence to moderate certainty due to the bias risk. We gathered data on all primary outcomes from all trials. Seventy-one of 320 participants allocated to band ligation compared to 129 of 317 participants allocated to no intervention died (RR 0.55, 95% CI 0.43 to 0.70; I2 = 0%; NNTTB = 6 persons). In addition, band ligation was associated with reduced risks of upper gastrointestinal bleeding (RR 0.44, 95% CI 0.28 to 0.72; 6 trials, 637 participants; I2 = 61%; NNTTB = 5 persons), serious adverse events (RR 0.55, 95% CI 0.43 to 0.70; 6 trials, 637 participants; I2 = 44%; NNTTB = 4 persons), and variceal bleeding (RR 0.43, 95% CI 0.27 to 0.69; 6 trials, 637 participants; I² = 56%; NNTTB = 5 persons). The non-serious adverse events reported in association with band ligation included oesophageal ulceration, dysphagia, odynophagia, retrosternal and throat pain, heartburn, and fever, and in the one trial involving participants with either small or large varices, the incidence of non-serious side effects in the banding group was much higher in those with small varices, namely ulcers: small versus large varices 30.5% versus 8.7%; heartburn 39.2% versus 17.4%. No trials reported on health-related quality of life.Two trials did not receive support from pharmaceutical companies; the remaining four trials did not provide information on this issue. This review found moderate-certainty evidence that, in patients with cirrhosis, band ligation of oesophageal varices reduces mortality, upper gastrointestinal bleeding, variceal bleeding, and serious adverse events compared to no intervention. It is unlikely that further trials of band ligation versus no intervention would be considered ethical.

Psychological therapies (remotely delivered) for the management of chronic and recurrent pain in children and adolescents

Background Chronic pain is common during childhood and adolescence and is associated with negative outcomes such as increased severity of pain, reduced function (e.g. missing school), and low mood (e.g. high levels of depression and anxiety). Psychological therapies, traditionally delivered face-to-face with a therapist, are efficacious at reducing pain intensity and disability. However, new and innovative technology is being used to deliver these psychological therapies remotely, meaning barriers to access to treatment such as distance and cost can be removed or reduced. Therapies delivered with technological devices, such as the Internet, computer-based programmes, smartphone applications, or via the telephone, can be used to deliver treatment to children and adolescents with chronic pain.

Interpreting survival outcomes for African-American (AA) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T (SIP-T) with number needed to treat to benefit (NNTB).

222 Background: AA men often present with more aggressive prostate cancer and are less likely to receive treatment, negatively affecting quality-of-life and overall survival (OS). Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Data from the PROCEED registry showed that OS for AA pts treated with SIP-T was 9.3 mo longer than OS for Caucasian pts. In a prior subgroup analysis of Phase III data, AA pts realized a 30.7-mo difference in OS with SIP-T vs. placebo (PBO). We calculated the NNTB to further interpret the OS benefit in AA pts. Methods: Data were pooled from 3 Phase III mCRPC SIP-T trials (D9901, D9902A, and IMPACT). The absolute risk reduction (ARR) is calculated from Kaplan-Meier estimates at 12-, 24-, and 36-mo for all SIP-T subjects, and an AA cohort, receiving ≥1 infusion. NNTB, the inverse of the ARR, represents the number of pts needed to be treated with SIP-T to prevent 1 additional death compared to PBO. All NNTB values are rounded up. Results: Of the 737 pooled mCRPC pts enrolled, 488 men were randomized to SIP-T (n=33 AA), and 249 to PBO. Baseline clinical characteristics between the SIP-T and PBO groups were well balanced; however, compared to overall SIP-T and PBO, AA SIP-T pts were more likely to have received prior chemotherapy, lower hemoglobin, and better performance status. The NNTB at 12-mo was the same (13) for both the pooled SIP-T and AA treated cohort. At 24-mo, the NNTB values were 10 for pooled and 5 for AA. At 36-mo, an NNTB of 8 (pooled) and 3 (AA) SIP-T treatments prevented 1 additional death (Table). Conclusions: This NNTB analysis shows a favorable survival benefit for AA men treated with SIP-T and all treated SIP-T subjects. NNTB values declined over 3-years, suggesting durability of clinical benefit with SIP-T, and that it may address a known survival disparity in AA with prostate cancer. Studies with larger sample sizes may confirm if AA pts derive a greater OS benefit from SIP-T. Clinical trial information: NCT00065442. [Table: see text]

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction.

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction. There is uncertainty whether these treatments are beneficial for people with heart failure with preserved ejection fraction and a comprehensive review of the evidence is required. To assess the effects of beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with heart failure with preserved ejection fraction. We searched CENTRAL, MEDLINE, Embase and two clinical trial registries on 25 July 2017 to identify eligible studies. Reference lists from primary studies and review articles were checked for additional studies. There were no language or date restrictions. We included randomised controlled trials with a parallel group design enrolling adult participants with heart failure with preserved ejection fraction, defined by a left ventricular ejection fraction of greater than 40 percent. Two review authors independently selected studies for inclusion and extracted data. The outcomes assessed included cardiovascular mortality, heart failure hospitalisation, hyperkalaemia, all-cause mortality and quality of life. Risk ratios (RR) and, where possible, hazard ratios (HR) were calculated for dichotomous outcomes. For continuous data, mean difference (MD) or standardised mean difference (SMD) were calculated. We contacted trialists where neccessary to obtain missing data. 37 randomised controlled trials (207 reports) were included across all comparisons with a total of 18,311 participants.Ten studies (3087 participants) investigating beta-blockers (BB) were included. A pooled analysis indicated a reduction in cardiovascular mortality (15% of participants in the intervention arm versus 19% in the control arm; RR 0.78; 95% confidence interval (CI) 0.62 to 0.99; number needed to treat to benefit (NNTB) 25; 1046 participants; 3 studies). However, the quality of evidence was low and no effect on cardiovascular mortality was observed when the analysis was limited to studies with a low risk of bias (RR 0.81; 95% CI 0.50 to 1.29; 643 participants; 1 study). There was no effect on all-cause mortality, heart failure hospitalisation or quality of life measures, however there is uncertainty about these effects given the limited evidence available.12 studies (4408 participants) investigating mineralocorticoid receptor antagonists (MRA) were included with the quality of evidence assessed as moderate. MRA treatment reduced heart failure hospitalisation (11% of participants in the intervention arm versus 14% in the control arm; RR 0.82; 95% CI 0.69 to 0.98; NNTB 41; 3714 participants; 3 studies; moderate-quality evidence) however, little or no effect on all-cause and cardiovascular mortality and quality of life measures was observed. MRA treatment was associated with a greater risk of hyperkalaemia (16% of participants in the intervention group versus 8% in the control group; RR 2.11; 95% CI 1.77 to 2.51; 4291 participants; 6 studies; high-quality evidence).Eight studies (2061 participants) investigating angiotensin converting enzyme inhibitors (ACEI) were included with the overall quality of evidence assessed as moderate. The evidence suggested that ACEI treatment likely has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalisation, or quality of life. Data for the effect of ACEI on hyperkalaemia were only available from one of the included studies.Eight studies (8755 participants) investigating angiotensin receptor blockers (ARB) were included with the overall quality of evidence assessed as high. The evidence suggested that treatment with ARB has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalisation, or quality of life. ARB was associated with an increased risk of hyperkalaemia (0.9% of participants in the intervention group versus 0.5% in the control group; RR 1.88; 95% CI 1.07 to 3.33; 7148 participants; 2 studies; high-quality evidence).We identified a single ongoing placebo-controlled study investigating the effect of angiotensin receptor neprilysin inhibitors (ARNI) in people with heart failure with preserved ejection fraction. There is evidence that MRA treatment reduces heart failure hospitalisation in heart failure with preserverd ejection fraction, however the effects on mortality related outcomes and quality of life remain unclear. The available evidence for beta-blockers, ACEI, ARB and ARNI is limited and it remains uncertain whether these treatments have a role in the treatment of HFpEF in the absence of an alternative indication for their use. This comprehensive review highlights a persistent gap in the evidence that is currently being addressed through several large ongoing clinical trials.

Grommets (ventilation tubes) for recurrent acute otitis media in children.

Acute suppurative otitis media is one of the most common infectious diseases in childhood. Recurrent acute otitis media is defined for the purposes of this review as either three or more acute infections of the middle ear cleft in a six-month period, or at least four episodes in a year. Strategies for managing the condition include the assessment and modification of risk factors where possible, repeated courses of antibiotics for each new infection, antibiotic prophylaxis and the insertion of ventilation tubes (grommets).To establish whether ventilation tube insertion reduces the frequency of episodes of recurrent acute otitis media and the proportion of children with symptoms of ear disease.We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1 2008), MEDLINE (1950 to 2008), EMBASE (1974 to 2008), CINAHL, mRCT (the metaRegister of Controlled Trials for ongoing/unpublished trials), NRR (National Research Register), LILACs, KoreaMed, IndMed, PakMediNet, Zetoc, ISI Proceedings and Cambridge Scientific Abstracts. Reference lists of articles retrieved from the electronic searches were scanned for further trials. Systematic reviews and other meta-analyses were also searched for and their reference lists scanned. Contact was sought with authors of published trials and other experts in the field. The date of the last search was March 2008.No trials that included a treatment and a control group that met the inclusion criteria were excluded. Abstracts were screened and full text articles of studies that met our inclusion criteria obtained. Two authors independently applied the inclusion criteria. Studies included in the review underwent quality assessment performed independently by all authors adapting the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions.Data were extracted independently by the authors and synthesised descriptively. Five randomised controlled trials were identified, of which two fulfilled the inclusion criteria.Two studies involving 148 children were included in the review. One of these studies, involving 95 children, showed that ventilation tube insertion leads to a mean reduction of 1.5 episodes of acute otitis media in the first six months after treatment. This study also showed a significant increase in the proportion of children with no episodes of AOM (p < 0.001) in the ventilation tube group. The other included study also found a higher proportion of patients in the ventilation tube group had no episodes of AOM in the six months after intervention, but the difference did not reach statistical significance (p = 0.16).Ventilation tubes have a significant role in maintaining a 'disease-free' state in the first six months after insertion. Further research is required to investigate the effect beyond six months. Clinicians should consider the possible adverse effects of grommet insertion before surgery is undertaken.

Certolizumab pegol (CDP870) for rheumatoid arthritis in adults.

Tumour necrosis factor (TNF)-alpha inhibitors are beneficial for the treatment of rheumatoid arthritis (RA) for reducing the risk of joint damage, improving physical function and improving the quality of life. This review is an update of the 2014 Cochrane Review of the treatment of RA with certolizumab pegol. To assess the clinical benefits and harms of certolizumab pegol (CZP) in people with RA who have not responded well to conventional disease-modifying anti-rheumatic drugs (DMARDs). We searched the Cochrane Central Register of Controlled Trials (CENTRAL: Cochrane Library 2016, Issue 9), MEDLINE, Embase, Web of Knowledge, reference lists of articles, clinicaltrials.gov and ICTRP of WHO. The searches were updated from 2014 (date of the last search for the previous version) to 26 September 2016. Randomised controlled trials that compared certolizumab pegol with any other agent, including placebo or methotrexate (MTX), in adults with active RA, regardless of current or prior treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs), such as MTX. Two review authors independently checked search results, extracted data and assessed trial quality. We resolved disagreements by discussion or referral to a third review author. We included 14 trials in this update, three more than previously. Twelve trials (5422 participants) included measures of benefit. We pooled 11 of them, two more than previously. Thirteen trials included information on harms, (5273 participants). The duration of follow-up varied from 12 to 52 weeks and the range of doses of certolizumab pegol varied from 50 to 400 mg given subcutaneously. In Phase III trials, the comparator was placebo plus MTX in seven trials and placebo in five. In the two Phase II trials the comparator was only placebo.The approved dose of certolizumab pegol, 200 mg every other week, produced clinically important improvements at 24 weeks for the following outcomes:- American College of Rheumatology (ACR) 50% improvement (pain, function and other symptoms of RA): 25% absolute improvement (95% confidence interval (CI) 20% to 33%); number need to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 5); risk ratio (RR) 3.80 (95% CI 2.42 to 5.95), 1445 participants, 5 studies.- The Health Assessment Questionnaire (HAQ): -12% absolute improvement (95% CI -9% to -14%); NNTB of 8 (95% CI 7 to 11); mean difference (MD) - 0.35 (95% CI -0.43 to -0.26; 1268 participants, 4 studies) (scale 0 to 3; lower scores mean better function).- Proportion of participants achieving remission (Disease Activity Score (DAS) < 2.6) absolute improvement 10% (95% CI 8% to 16%); NNTB of 8 (95% CI 6 to 12); risk ratio (RR) 2.94 (95% CI 1.64 to 5.28), 2420 participants, six studies.- Radiological changes: erosion score (ES) absolute improvement -0.29% (95% CI -0.42% to -0.17%); NNTB of 6 (95% CI 4 to 10); MD -0.67 (95% CI -0.96 to -0.38); 714 participants, two studies (scale 0 to 230), but not a clinically important difference.-Serious adverse events (SAEs) were statistically but not clinically significantly more frequent for certolizumab pegol (200 mg every other week) with an absolute rate difference of 3% (95% CI 1% to 4%); number needed to treat for an additional harmful outcome (NNTH) of 33 (95% CI 25 to 100); Peto odds ratio (OR) 1.47 (95% CI 1.13 to 1.91); 3927 participants, nine studies.There was a clinically significant increase in all withdrawals in the placebo groups (for all doses and at all follow-ups) with an absolute rate difference of -29% (95% CI -16% to -42%), NNTH of 3 (95% CI 2 to 6), RR 0.47 (95% CI 0.39 to 0.56); and there was a clinically significant increase in withdrawals due to adverse events in the certolizumab groups (for all doses and at all follow-ups) with an absolute rate difference of 2% (95% CI 0% to 3%); NNTH of 58 (95% CI 28 to 329); Peto OR 1.45 (95% CI 1.09 to 1.94) 5236 participants Twelve studies.We judged the quality of evidence to be high for ACR50, DAS remission, SAEs and withdrawals due to adverse events, and moderate for HAQ and radiological changes, due to concerns about attrition bias. For all withdrawals we judged the quality of evidence to be moderate, due to inconsistency. The results and conclusions did not change from the previous review. There is a moderate to high certainty of evidence from randomised controlled trials that certolizumab pegol, alone or combined with methotrexate, is beneficial in the treatment of RA for improved ACR50 and health-related quality of life, an increased chance of remission of RA, and reduced joint damage as seen on x-ray. Fewer people stopped taking their treatment, but most of these who did stopped due to serious adverse events. Adverse events were more frequent with active treatment. We found a clinically but not statistically significant risk of serious adverse events.

Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults.

Asthma severity and control can be measured both subjectively and objectively. Sputum analysis for evaluation of percentage of sputum eosinophilia directly measures airway inflammation, and is one method of objectively monitoring asthma. Using sputum analysis to adjust or tailor asthma medications is potentially superior to traditional methods based on symptoms and spirometry. To evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to traditional methods (usually symptom-based with or without spirometry/peak flow) for asthma-related outcomes in children and adults. We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trials' registries, and reference lists of articles. The last search was conducted in February 2017. All randomised controlled comparisons of adjustment of asthma therapy based on sputum eosinophils compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). Results of searches were reviewed against pre-determined criteria for inclusion. In this update, two reviewers selected relevant studies, independently assessed trial quality and extracted the data. We contacted authors for further information when relevant. We analysed data as 'treatment received' and performed sensitivity analyses. Three new studies were added in this update, resulting in a total of six included studies (five in adults and one involving children/adolescents). These six studies were clinically and methodologically heterogeneous (use of medications, cut-off for percentage of sputum eosinophils and definition of asthma exacerbation). Of 374 participants randomised, 333 completed the trials. In the meta-analysis, there was a significant reduction in the occurrence of any exacerbations when treatment was based on sputum eosinophil counts, compared to that based on clinical symptoms with or without lung function; pooled odds ratio (OR) was 0.57 (95% confidence interval (CI) 0.38 to 0.86). The risk of having one or more exacerbations over 16 months was 82% in the control arm and 62% (95% CI 49% to 74%) in the sputum strategy arm, resulting in a number needed to treat to benefit (NNTB) of 6 (95% CI 4 to 13).There were also differences between the groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids and hospitalisations: the risk of one or more hospitalisations over 16 months was 24% in controls compared to 8% (95% CI 3% to 21%) in the sputum arm. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was also similar in both groups. However sputum induction was not always possible. The included studies did not record any adverse events.One study was not blinded and thus was considered to have a high risk of bias. However, when this study was removed in a sensitivity analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant between groups. The GRADE quality of the evidence ranged from moderate (for the outcomes 'Occurrence of any exacerbation' and 'Hospitalisation' ) to low (for the outcome 'Mean dose of inhaled corticosteroids per person per day') due to the inconsistency in defining exacerbations and the small number of hospital admissions. In this updated review, tailoring asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. Adults with frequent exacerbations and severe asthma may derive the greatest benefit from this additional monitoring test, although we were unable to confirm this through subgroup analysis. There is insufficient data available to assess tailoring asthma medications based on sputum eosinophilia in children.Further robust RCTs need to be undertaken and these should include participants with different underlying asthma severities and endotypes.

Celecoxib for rheumatoid arthritis.

Celecoxib for rheumatoid arthritis.

Number needed to treat (NNT) in clinical literature: an appraisal

BackgroundThe number needed to treat (NNT) is an absolute effect measure that has been used to assess beneficial and harmful effects of medical interventions. Several methods can be used to calculate NNTs, and they should be applied depending on the different study characteristics, such as the design and type of variable used to measure outcomes. Whether or not the most recommended methods have been applied to calculate NNTs in studies published in the medical literature is yet to be determined. The aim of this study is to assess whether the methods used to calculate NNTs in studies published in medical journals are in line with basic methodological recommendations.MethodsThe top 25 high-impact factor journals in the “General and/or Internal Medicine” category were screened to identify studies assessing pharmacological interventions and reporting NNTs. Studies were categorized according to their design and the type of variables. NNTs were assessed for completeness (baseline risk, time horizon, and confidence intervals [CIs]). The methods used for calculating NNTs in selected studies were compared to basic methodological recommendations published in the literature. Data were analyzed using descriptive statistics.ResultsThe search returned 138 citations, of which 51 were selected. Most were meta-analyses (n = 23, 45.1%), followed by clinical trials (n = 17, 33.3%), cohort (n = 9, 17.6%), and case–control studies (n = 2, 3.9%). Binary variables were more common (n = 41, 80.4%) than time-to-event (n = 10, 19.6%) outcomes. Twenty-six studies (51.0%) reported only NNT to benefit (NNTB), 14 (27.5%) reported both NNTB and NNT to harm (NNTH), and 11 (21.6%) reported only NNTH. Baseline risk (n = 37, 72.5%), time horizon (n = 38, 74.5%), and CI (n = 32, 62.7%) for NNTs were not always reported. Basic methodological recommendations to calculate NNTs were not followed in 15 studies (29.4%). The proportion of studies applying non-recommended methods was particularly high for meta-analyses (n = 13, 56.5%).ConclusionsA considerable proportion of studies, particularly meta-analyses, applied methods that are not in line with basic methodological recommendations. Despite their usefulness in assisting clinical decisions, NNTs are uninterpretable if incompletely reported, and they may be misleading if calculating methods are inadequate to study designs and variables under evaluation. Further research is needed to confirm the present findings.