Context: This is an updated version of a Cochrane Review last updated in 2020. Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. In nearly 30% of cases, epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is a second-generation antiseizure medication. When used as an add-on (in combination with other antiseizure medications), lamotrigine can reduce seizures, but with some adverse effects.

To evaluate the benefits and harms of add-on lamotrigine, compared with add-on placebo or no add-on treatment in people with drug-resistant focal epilepsy.

We included randomised controlled trials (RCTs) that investigated add-on lamotrigine versus add-on placebo or no add-on treatment in people of any age with drug-resistant focal epilepsy. We used data from the first period of eligible cross-over trials.

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group.

Abstract:
To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures.

Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children.

We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period.

Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy.

Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.

Lamotrigine extended-release as adjunctive therapy for partial seizures.

Abstract:
To evaluate the efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for partial seizures in epilepsy.

Patients more than 12 years old diagnosed with epilepsy with partial seizures and taking one to two baseline antiepileptic drugs were randomized to adjunctive once-daily lamotrigine XR or placebo in a double-blind, parallel-group trial. The study comprised a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase during which doses of study medication and concomitant antiepileptic drugs were maintained.

Of the 243 randomized patients, 239 (118 lamotrigine XR, 121 placebo) entered the escalation phase and received study medication. Lamotrigine XR was more effective than placebo with respect to median percent reduction from baseline in weekly partial seizure frequency (primary endpoint-entire 19-week treatment phase: 46.6% vs 24.5%, p = 0.0001 [corrected] via Wilcoxon test; escalation phase: 29.8% vs 15.6%, p = 0.027; maintenance phase: 58.4% vs 26.8%, p [corrected] < 0.0001). The percentage of patients with >or=50% reduction in partial seizure frequency (44.0% vs 20.8%, p = 0.0002) [corrected] and time to >or=50% reduction in partial seizure frequency (p = 0.0001) [corrected] also favored lamotrigine XR over placebo. A similar pattern of results was observed for secondarily generalized seizures. The most common adverse events were headache (lamotrigine XR 16%, placebo 18%) [corrected] and dizziness (lamotrigine XR 19%, [corrected] placebo 5%). Differences between lamotrigine XR and placebo on health outcomes measures were not significant.

Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced partial seizure frequency and was well tolerated in this double-blind study. Results support the clinical utility of this new once-daily formulation.

Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months.

Abstract:
This randomized, double-blind, placebo-controlled trial was conducted to assess the efficacy and tolerability of adjunctive lamotrigine for the treatment of partial seizures in infants aged 1 to 24 months.

The study used a responder-enriched design in which all patients received adjunctive lamotrigine during an open-label phase (n = 177; maximum maintenance dose 5.1 mg/kg/day for those on non-enzyme-inducing antiepileptic drugs [AEDs] or valproate and 15.6 mg/kg/day for those on enzyme-inducing AEDs). Patients meeting response criteria were randomly assigned to double-blind treatment for up to 8 weeks with continued lamotrigine (n = 19) or to withdrawal from lamotrigine (placebo; n = 19) while background AEDs were maintained.

The proportion of treatment failures (patients who met escape criteria or withdrew before completing the double-blind phase) was lower with lamotrigine (58%) than with placebo (84%). This finding was not significant in the primary analysis (two-sided chi(2) test [primary endpoint]). A post hoc sensitivity analysis of the primary endpoint was also performed (p = 0.045 by one-sided, mid-p corrected Fisher exact test). The median time to meet escape criteria was longer with lamotrigine (42 days) than with placebo (22 days) (p = 0.059). During the last 28 days of the open-label phase, 53% of the patients had a >or=50% reduction in frequency of partial seizures with lamotrigine. Additional reduction in partial seizure frequency was observed during the double-blind phase compared with the last 4 weeks of the open-label phase among those randomly assigned to lamotrigine (32% with a >or=25% reduction) but not those randomly assigned to placebo (5% with a >or=25% reduction). Lamotrigine was well tolerated, with an adverse event profile comparable to that observed in older pediatric patients.

Lamotrigine was well tolerated, and the data indicate that it may be efficacious in the treatment of partial seizures in infants aged 1 to 24 months.

A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures.

Abstract:
This study assessed the comparative efficacy of pregabalin for refractory partial seizures.

Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day.

During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of -20.0% (p=.001) versus placebo, and -9.7% (p=.080) versus lamotrigine. The responder rate (> or =50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p=.007) and lamotrigine (36% vs 24%; p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine.

Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.

A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures.

Abstract: Efficacy and safety of lamotrigine (LTG) as add-on therapy was assessed in a randomised double-blind placebo-controlled trial of this drug in 23 adult patients with refractory partial seizures. Fifteen patients showed an improvement on LTG treatment, with a greater than 50% decrease in total seizure count in 7 patients. Fourteen patients experienced fewer simple and complex partial seizures, with 8 patients benefitting by more than a 50% decrease in seizure frequency. The drug was well tolerated over the 2 month treatment period. The plasma concentration of concomitant antiepileptic drugs remained unchanged. No haematological or chemical abnormalities were noted.

Gabapentin and lamotrigine in Indian patients of partial epilepsy refractory to carbamazepine.

Abstract: 52 patients (25 males and 27 females) suffering from refrectory partial seizures, of not more than two years duration and on carbamazepine monotherapy were enrolled in this study. Patients were randomly put on gabapentin (19 males and 8 females) or lamotrigine (6 males and 19 females) as add on therapy. The efficacy of the drugs was assessed by the seizure frequency, pattern of seizures and seizure free interval. The safety was evaluated from the biochemical investigations and the adverse effects observed or reported by the patients during the course of the study. The average frequency of basal partial seizures was 6.26+3.86 and 5.04+2.47 which decreased significantly (p<. 001) after 12 weeks of add on therapy to 1.75+2.16. and 1.68+2.94 in the GBP and LTG group respectively. However, there was no significant difference between the two drugs after 12 weeks of add on therapy. The PCB (primary change in basal seizure frequency) values decreased to -72+34.92 and -76.22+29.68 in the GBP and LTG group respectively. The difference in these two groups was not significant. The responder rate was 77.7% and 92% respectively in GBP and LTG group respectively. GBP was found to be more effective in partial seizures with secondarily generalization while LTG was effective in all subtypes of partial seizures. The abnormal scalp EEG was recorded in 33.3% (9 of 27 patients) in GBP group and 40 %( 10 of 25 patients) in LTG group and it did not revert to normal in 33.3% and 40% of patients in either of groups (GBP/LTG). Minor side effects which were self limiting were noticed in 80% in groups I and 74% were groups II.

Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study.

Abstract: Efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for primary generalized tonic-clonic (PGTC) seizures in epilepsy were evaluated. Patients (n = 153) ≥ 13 years old diagnosed with epilepsy with PGTC seizures were randomized to once-daily adjunctive lamotrigine XR or placebo in a double-blind, parallel-group trial comprising a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase. Lamotrigine XR was more effective than placebo with respect to median percentage reduction from baseline in weekly PGTC seizure frequency (primary endpoint-19-week treatment phase: 75.4% vs 32.1%, P<0.0001; escalation phase: 61.9% vs 30.6%, P = 0.0016; maintenance phase: 89.7% vs 33.3%, P<0.0001). Lamotrigine XR was more effective than placebo with respect to the percentage of patients with ≥50% reduction in PGTC seizure frequency. Significant separation from placebo for ≥50% reduction in PGTC seizures was observed beginning on treatment day 8. The most common adverse event was headache (lamotrigine XR 14%, placebo 16%).

Cognitive effects of lamotrigine versus topiramate as adjunctive therapy in older adults with epilepsy.

Abstract: Older individuals may be more susceptible to cognitive side effects of antiepileptic drugs than are younger adults. This randomized, double-blind study compared the cognitive effects of lamotrigine (median maintenance dosage, 500.0 mg/d) and topiramate (median maintenance dosage, 300.0 mg/d) as adjunctive therapy for 16 weeks in patients ≥50 years of age. Fifty-one patients (lamotrigine, n=25; topiramate, n=26) were enrolled, and 28 patients (lamotrigine, n=15; topiramate, n=13) completed the study. In a combined analysis of all cognitive tests performed, no significant differences between treatment groups were noted. However, analyses of individual cognitive test results revealed that lamotrigine-treated patients had significantly better results on the Controlled Oral Word Association Test and the Symbol-Digit Modalities Test, whereas topiramate-treated patients had significantly more favorable results on the Digit Cancellation Test and the Rey Auditory-Verbal Learning Test. Larger studies are needed to further clarify the differences in the cognitive effects of lamotrigine and topiramate in older patients.

Influence of concomitant antiepileptic drugs on plasma lamotrigine concentration in adult Japanese epilepsy patients.

Abstract: Lamotrigine (LTG) is an antiepileptic drug (AED) that was approved in Japan in 2008. We evaluated the influence of AEDs that induce hepatic enzymes (including phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ)), valproic acid (VPA), and various combinations of these drugs, on plasma LTG concentration in adult Japanese epilepsy patients. A total of 621 patients (mean age 34.4±11.8 years) were evaluated retrospectively. We calculated the concentration to dose ratio (CD ratio) for LTG with different AED regimens, and employed multiple regression analysis to determine factors influencing the LTG concentration. There was a linear correlation between the dose and concentration of LTG in patients treated with LTG (group I), LTG+VPA (group II), LTG+inducers (group III), or LTG+VPA+inducers (group IV). The mean CD ratio of patients on LTG monotherapy was 1.43±0.4 (μg/mL)/(mg/kg). When LTG was combined with VPA, the CD ratio increased about 2.2-fold, but there was no significant correlation between the CD ratio and VPA concentration. The mean CD ratios calculated in patients receiving LTG+PHT, LTG+PB, and LTG+CBZ were 0.56, 0.84, and 0.91, respectively. Addition of PHT significantly reduced the CD ratio in a concentration-dependent manner, in comparison with PB and CBZ (p<0.005 and p<0.001, respectively). Stepwise multiple regression analysis showed that the coefficient of determination of groups I, II, III, and IV were 0.94, 0.94, 0.90, and 0.91, respectively. In the clinical setting, these findings can help to estimate LTG concentrations and predict the inducing or inhibiting effects of concomitant AEDs.

Analysis of three lamotrigine extended-release clinical trials: comparison of pragmatic ITT and LOCF methodologies.

Abstract: Early withdrawal of patients from a clinical trial can compromise the robustness of the data by introducing bias into the analysis. This is most commonly addressed by using the "intent to treat" (ITT) population and "last observation carried forward" (LOCF) methodology, where a patient's last assessment is carried forward. This can lead to overstatement of treatment efficacy especially if events indicative of treatment failure are infrequent. An alternative methodology, labeled "pragmatic ITT" (P-ITT), requires patients to have a positive outcome and to complete the trial in order to be considered a treatment success by that outcome measure. Data from 3 randomized multicenter lamotrigine extended-release (LTG XR) trials were analyzed and response (proportions seizure-free and with 50% response) were compared using LOCF and P-ITT methodologies. In 2 of the 3 trials, a lower response for both seizure freedom and 50% response was seen during the Maintenance phase using the P-ITT methodology. In the trial that did not show a difference, only a small number of patients withdrew early, thus negating the benefit brought by the P-ITT method. Differences between methodologies were not noted when evaluation was applied to the entire treatment period, most likely a reflection of the fact that a therapeutic dose of lamotrigine is not rapidly achieved. We propose that the P-ITT may be a simpler, more informative method for evaluating the effectiveness of a drug, especially in comparison to another active drug(s).


Context: Anticholinergics are medications that block the action of acetylcholine in the central or peripheral nervous system. Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the anticholinergic burden. A high anticholinergic burden may cause cognitive impairment in people who are otherwise cognitively healthy, or cause further cognitive decline in people with pre-existing cognitive problems. Reducing anticholinergic burden through deprescribing interventions may help to prevent onset of cognitive impairment or slow the rate of cognitive decline.

Primary objective • To assess the efficacy and safety of anticholinergic medication reduction interventions for improving cognitive outcomes in cognitively healthy older adults and older adults with pre-existing cognitive issues. Secondary Objectives • To compare the effectiveness of different types of reduction interventions (e.g. pharmacist-led versus general practitioner-led, educational versus audit and feedback) for reducing overall anticholinergic burden. • To establish optimal duration of anticholinergic reduction interventions, sustainability, and lessons learnt for upscaling • To compare results according to differing anticholinergic scales used in medication reduction intervention trials • To assess the efficacy of anticholinergic medication reduction interventions for improving other clinical outcomes, including mortality, quality of life, clinical global impression, physical function, institutionalisation, falls, cardiovascular diseases, and neurobehavioral outcomes.

We included randomised controlled trials (RCTs) of interventions that aimed to reduce anticholinergic burden in older people and that investigated cognitive outcomes.

Cognitive effects of reducing anticholinergic drug burden in a frail elderly population: a randomized controlled trial.

Abstract:
Observational studies report a relationship between anticholinergic drug scale (ADS) score and cognitive function. This study investigated whether a reduced ADS score improved cognitive function in a frail elderly population.

This randomized, controlled, single-blinded trial, recruited long-term residents with an ADS score of greater than or equal to 3 from 22 nursing homes in Norway. The participants were randomly allocated (1:1) to intervention or control. The intervention was a pharmacist-initiated reduction of ADS score after multidisciplinary drug reviews. Primary end point was Consortium to Establish a Registry for Alzheimer's Disease 10-wordlist test for immediate recall. Secondary end points were Mini-Mental Sate Examination, delayed recall and recognition of words, saliva flow, and serum anticholinergic activity (SAA).The participants were retested after 4 and 8 weeks, and the study groups were compared after adjusting for baseline differences.

Eighty-seven patients were included. The median ADS score was reduced by 2 units (p < .0001) in the intervention group and remained unchanged in the control group. After 8 weeks, the adjusted mean difference in immediate recall was 0.54 words between the intervention and control group (95% confidence interval [CI]: -0.91, 2.05; p = .48). The study groups did not differ significantly in any of the other cognitive end points, salvia flow, or SAA at either follow-up (p > .18).

Pharmacist-initiated drug changes significantly reduced ADS score but did not improve cognitive function in nursing home residents. Moreover, the drug changes did not reduce SAA or mouth dryness significantly, which might indicate limited applicability of the ADS score to prevent prescription risks in this population.

The relationship of serum anticholinergic activity to mental status performance in an elderly nursing home population.

Abstract: Adverse drug reactions among elderly patients pose a significant clinical problem. The authors used a serum radioreceptor assay [RRA] to quantify drug-induced muscarinic blockade in 34 randomly selected nursing home residents. A random intervention group and the nonintervention control subjects were then retested 4 weeks later. The reduction of serum antimuscarinic activity (as determined by RRA) did relate to changes on several measures of cognitive function. A calculated "antimuscarinic index" lost significance with the RRA following intervention and may have overestimated the impact of a dosage reduction.

Reducing the anticholinergic and sedative load in older patients on polypharmacy by pharmacist-led medication review: a randomised controlled trial.

Abstract:
To evaluate if a pharmacist-led medication review is effective at reducing the anticholinergic/sedative load, as measured by the Drug Burden Index (DBI).

Randomised controlled single blind trial.

15 community pharmacies in the Northern Netherlands.

157 community-dwelling patients aged ≥65 years who used ≥5 medicines for ≥3 months, including at least one psycholeptic/psychoanaleptic medication and who had a DBI≥1.

A medication review by the community pharmacist in collaboration with the patient's general practitioner and patient.

The primary outcome was the proportion of patients whose DBI decreased by at least 0.5. Secondary outcomes were the presence of anticholinergic/sedative side effects, falls, cognitive function, activities of daily living, quality of life, hospital admission and mortality. Data were collected at baseline and 3 months follow-up.

Mean participant age was 75.7 (SD, 6.9) years in the intervention arm and 76.6 (SD, 6.7) years in the control arm, the majority were female (respectively 69.3% and 72.0%). Logistic regression analysis showed no difference in the proportion of patients with a≥0.5 decrease in DBI between intervention arm (17.3%) and control arm (15.9%), (OR 1.04, CI 0.47 to 2.64, p=0.927). Intervention patients scored higher on the Digit Symbol Substitution Test, measure of cognitive function (OR 2.02, CI 1.11 to 3.67, p=0.021) and reported fewer sedative side effects (OR 0.61, CI 0.40 to 0.94, p=0.024) at follow-up. No significant difference was found for other secondary outcomes.

Pharmacist-led medication review as currently performed in the Netherlands was not effective in reducing the anticholinergic/sedative load, measured with the DBI, within the time frame of 3 months. Preventive strategies, signalling a rising load and taking action before chronic use of anticholinergic/sedative medication is established may be more successful.

NCT02317666.

Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson's disease. A follow-up study of untreated patients.

Abstract: The cognitive performance of a group of 82 newly diagnosed patients with Parkinson's disease who had never been treated was reassessed approximately 4 mths after randomization to one of three monotherapies (levodopa, bromocriptine or anticholinergic drugs). Dopaminergic and anticholinergic treatments both led to improvement in motor control but their effects upon cognitive performance dissociated. Anticholinergic drugs produced impairment in processes underlying the immediate registration of information whilst dopaminergic therapy produced improvement on a task dependent on working memory and cognitive sequencing. Other cognitive measures showed no change on treatment. The deficits that were affected by cholinergic and dopaminergic modulation are those that were most compromised in the early, untreated state in Parkinson's disease. The data support the notion that cognitive impairment in Parkinson's disease is multifactorial in origin: short-term memory processes are served by both dopaminergic and cholinergic subcortico-frontal systems but much of the cognitive impairment of Parkinson's disease is independent of this subcortical neurochemical pathology and may be due to early neuronal dysfunction within the cerebral cortex.

Effects of discontinuation of long-term anticholinergic treatment in elderly schizophrenia patients.

Abstract: Anticholinergic medication (ACM) is frequently used in psychiatry to treat the side-effects of D2 blocking agents. However, ACM is not without adverse effects and, in the elderly, cognitive and memory impairments have been emphasized. The aim of this study was to evaluate the effects of discontinuation of ACM on cognitive functions in a group of elderly chronic schizophrenia patients. Twenty-seven elderly patients (age 60 years or older), who were diagnosed as suffering from schizophrenia (DSM-IV) and receiving ACM in addition to antipsychotic treatment, were enrolled. Before and after ACM was discontinued, the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale was administered. Twenty-one patients completed the study. All were receiving Akineton (biperiden), 2-6 mg daily before the study. Significant improvement in the ADAS-Cog total score was demonstrated (P < 0.03), as well as in the ideational praxia and orientation subscales. Improvement was correlated with the previous dose of biperidin. No adverse events or emergent extrapyramidal symptoms were noted. Discontinuation of ACM may be warranted in chronic schizophrenia patients since it may improve cognitive functioning with no adverse effects.

Do anticholinergics affect reaction time? A possible impact on the course of rehabilitation.

Abstract:
To assess if oxybutynin and tolterodine have an effect on simple reaction time in healthy volunteers.

Simple reaction time was evaluated before and 90 minutes after the oral administration of oxybutynin and tolterodine in a cross-over design. Twenty seven healthy volunteers, aged 26 to 48 years, were included in the study. The electromyographic activity of the flexor digitorum superficialis muscle that was used for the response was recorded, and premotor time was measured.

The mean age of the study group was 33.1 ± 7.4 years. Mean premotor times before oxybutynin and before tolterodine administration were statistically non-significant. Mean premotor times after the administration of oxybutynin and tolterodine were significantly longer than the initial premotor times (p = 0.003).

The results of the study showed that oxybutynin and tolterodine prolonged the simple reaction time. The prolonged simple reaction time may suggest a perceptive impairment. The potential for perceptive impairment as a side effect of oxybutynin and tolterodine might suggest a negative impact on the rehabilitation interventions and the activities of daily living because of central nervous system effects.

Effect of anticholinergic use for the treatment of overactive bladder on cognitive function in postmenopausal women.

Abstract:
Overactive bladder (OAB) is a common condition affecting the elderly. The mainstay of treatment for OAB is medical therapy with anticholinergics. However, adverse events have been reported with this class of drugs, including cognitive changes.

The objective of this study was to investigate the effect of an anticholinergic medication, trospium chloride, on cognitive function in postmenopausal women being treated for OAB.

This was a prospective cohort study conducted at a urogynaecology clinic at one academic medical centre from January to December 2010, with 12-week follow-up after medication initiation. Women aged 55 years or older seeking treatment for OAB and opting for anticholinergic therapy were recruited. Baseline cognitive function was assessed via the Hopkins Verbal Learning Test-Revised Form (HVLT-R) [and its five subscales], the Orientation, Memory & Concentration (OMC) short form, and the Mini-Cog evaluation. After initiation of trospium chloride extended release, cognitive function was reassessed at Day 1, Week 1, Week 4 and Week 12. Bladder function was assessed via three condition-specific quality-of-life questionnaires. Secondary outcomes included change in bladder symptoms, correlation between cognitive and bladder symptoms, and overall medication compliance. The main outcome measure was change in HVLT-R score at Week 4 after medication initiation, compared with baseline (pre-medication) score.

Of 50 women enrolled, 35 completed the assessment. The average age was 70.4 years and 77.1% had previously taken anticholinergic medication for OAB. At enrollment 65.7% had severe overactive bladder and 71.4% had severe urge incontinence. Cognitive function showed an initial decline on Day 1 in HVLT-R total score (p = 0.037), HVLT-R Delayed Recognition subscale (p = 0.011) and HVLT-R Recognition Bias subscale (p = 0.01). At Week 1 the HVLT-R Learning subscale declined from baseline (p = 0.029). All HVLT-R scores normalized by Week 4. OMC remained stable throughout. The Mini-Cog nadired at a 90.9% pass rate at Week 4. OAB symptoms did not improve until Week 4, based on questionnaire scores (p < 0.05).

Cognitive function exhibited early changes after initiation of trospium chloride but normalized within 4 weeks. Cognitive changes occurred weeks prior to OAB symptom improvement. Surveillance for cognitive changes with anticholinergic use should be part of OAB management.

Potential benefits of reducing medication-related anticholinergic burden for demented older adults: a prospective cohort study.

Abstract:
Medication-related anticholinergic burden is a quality indicator for geriatric pharmacotherapy; however, little is known regarding the benefits of reducing anticholinergic burden for demented patients

Demented residents in a Veteran Home were enrolled for this study and an educational program was held for primary care physicians providing services at the Veterans Home. Residents were assigned to the intervention group if the primary care team could adhere to the research protocol and the remaining residents were assigned to the reference group receiving conventional care. Anticholinergic burden was estimated by Clinician-Rated Anticholinergic Score (CR-ACHS). Healthcare outcomes; for example, hospitalizations, mortality, cognitive and physical function, were compared between groups.

Overall, 53 of the 67 demented residents (mean age 83.4 ± 4.4 years) completed this study. Anticholinergic exposure was found in 38 participants (56.7%) at baseline, in which antipsychotics (n=29, 76.3%) and antidepressants (n=19, 50%) were the most common agents. Compared with participants in the reference group, CR-ACHS was significantly reduced in the intervention group at 12-week follow up (intervention group vs reference group=0.5 ± 1.1 vs 1.1 ± 1.3, P=0.021), whereas the mean Mini-Mental State Examination and Barthel Index were similar between groups. In contrast, no clinical complication was observed regarding medication adjustments during the study period.

Anticholinergic burden can be successfully and safely reduced through an educational program for primary care physicians, but the benefit of reducing anticholinergic burden remained unclear within the first 12 weeks. Further investigation is required to evaluate the long-term benefits of reducing anticholinergic burden for demented older adults.

Effects of anticholinergic challenge on psychopathology and cognition in drug-free patients with schizophrenia and healthy volunteers.

Abstract:
Many aspects of the neurobiology of schizophrenia, especially the physiological basis of the negative symptoms and associated cognitive deficits, remain inadequately understood. Tandon and Greden (1989) postulated a central role of dopaminergic/cholinergic imbalance in schizophrenia.

In light of this hypothesis, we elected to investigate the effects of anticholinergic challenge on psychopathology, cognition and attention in 12 unmedicated patients with schizophrenia and 12 healthy controls. The first examination occurred before any pharmacological intervention; the second examination was carried out immediately following an intravenous infusion of 5 mg biperiden, a centrally acting antimuscarinergic agent.

The biperiden challenge provoked a considerable increase in PANSS scores in both groups which was significantly more pronounced in patients (repeated measures analysis of variance (ANOVA) (rmANOVA): F(df) = 6.4(1,22); p = 0.019). The increase in the PANSS scores showed a significant negative correlation with age in patients. Biperiden caused considerable cognitive impairments in both groups. A significant group difference (rmANOVA) could be observed for TMT-B (F(df) = 11.29(1,22); p = 0.003).

The anticholinergic intervention caused more pronounced psychopathological and cognitive deteriorating effects in patients suffering from schizophrenia than in healthy volunteers. This could be related to the disrupted cholinergic transmission in schizophrenia. Our findings speak on behalf of the need of a more restrictive use of anticholinergics in psychiatric patients. The age-related attenuation of PANSS score increases in patients could be related to the age-dependent changes in dopamine dynamics and also to the age-associated decline of the availability of muscarinic receptors. Our results emphasise the need for further investigation of cholinergic disturbances in schizophrenia.

Effects of discontinuing anticholinergic treatment on movement disorders, cognition and psychopathology in patients with schizophrenia.

Abstract:
Physicians have prescribed anticholinergic agents such as benztropine, procyclidine, biperiden and trihexyphenidyl for treatment and prophylaxis of antipsychotic-induced extrapyramidal symptoms (EPS) for decades. Anticholinergic agents can however worsen tardive dyskinesia and cause many adverse effects, including cognitive impairment. Previous studies of anticholinergic discontinuation in patients with schizophrenia receiving antipsychotics have yielded a wide range of EPS relapse rates. Improvement in cognition after anticholinergic withdrawal was observed in some studies.

This study evaluated the effect of anticholinergic discontinuation on movement disorders, cognition and general psychopathology after a 4-week taper in 20 outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics.

Eighteen of twenty patients successfully discontinued their anticholinergic medication; two did not because of akathisia. Repeated measures analysis of variance did not show a significant effect of anticholinergic discontinuation on total Extrapyramidal Symptoms Rating Scale score or on the Parkinsonism, Akathisia, Dystonia or Tardive Dyskinesia subscales. However, significant improvement was found on the Brief Assessment of Cognition in Schizophrenia composite z score at weeks 6, 8 and 12 compared with baseline. Significant improvements were seen on the motor and the symbol-coding tasks. No significant effects were observed on the Positive and Negative Syndrome Scale, Clinical Global Impression - Severity and Clinical Global Impression - Improvement scales.

In this 12-week study of anticholinergic discontinuation in 20 outpatients with schizophrenia or schizoaffective disorder, gradual decrease and discontinuation of anticholinergics led to a positive effect on cognition. There were no adverse consequences on general psychopathology and no significant differences for 18 of 20 subjects on movement disorders.


Context: Aortic valve disease is a common condition easily treatable with cardiac surgery. This is conventionally performed by opening the sternum ('median sternotomy') and replacing the valve under cardiopulmonary bypass. Median sternotomy is well tolerated, but as less invasive options become available, the efficacy of limited incisions has been called into question. In particular, the effects of reducing the visibility and surgical access have raised safety concerns with regard to the placement of cannulae, venting of the heart, epicardial wire placement, and de-airing of the heart at the end of the procedure. These difficulties may increase operating times, affecting outcome. The benefits of smaller incisions are thought to include decreased pain; improved respiratory mechanics; reductions in wound infections, bleeding, and need for transfusion; shorter intensive care stay; better cosmesis; and a quicker return to normal activity. This is an update of a Cochrane review first published in 2017, with seven new studies.

To assess the effects of minimally invasive aortic valve replacement via a limited sternotomy versus conventional aortic valve replacement via median sternotomy in people with aortic valve disease requiring surgical replacement.

We included randomised controlled trials comparing aortic valve replacement via a median sternotomy versus aortic valve replacement via a limited sternotomy. We excluded trials that performed other minimally invasive incisions such as mini-thoracotomies, port access, transapical, transfemoral or robotic procedures. Although some well-conducted prospective and retrospective case-control and cohort studies exist, these were not included in this review.

Minimally invasive versus conventional aortic valve operations: a prospective study in 120 patients.

Abstract:
Risk evaluation comparing the minimally invasive and standard aortic valve operations has not been studied.

Four surgeons were randomly assigned to perform the minimally invasive (L-shaped sternotomy) (group 1) or the conventional (group 2) operation in 120 patients exclusively.

In both groups (n = 60) a CarboMedics prothesis was implanted in 90% of patients. There was no significant difference in the cross-clamping period (group 1, 60 minutes; range, 35 to 116 minutes), in the duration of extracorporal circulation (group 1, 84 minutes; range, 51 to 179 minutes) or in the time from skin-to-skin (group 1, 195 minutes; range, 145 to 466 minutes). Patients in group 1 were extubated earlier (p<0.001), the postoperative blood loss was less (p<0.001), and the need for analgesics was reduced (p<0.05). In 5 patients in group 1 a redo operation was required for bleeding (p>0.05), 3 patients in group 1 required a redo operation because of paravalvular leakage or endocarditis (p>0.05), the 30-day mortality rate was 1.6%. Overall the survival rate was 95% in group 1 and 97% in group 2 (mean follow-up, 294 days; range, 30 to 745 days).

The advantages of minimally invasive aortic valve operation include reduced trauma from incision and duration of ventilation, decreased blood loss and postoperative pain, the avoidance of groin cannulation, and a cosmetically attractive result. Simple equipment is used with a high degree of effectiveness and with no sacrifice of safety. Our study demonstrated the practicability and reliability of this new method.

Ministernotomy versus median sternotomy for aortic valve replacement: a prospective, randomized study.

Abstract:
Minimally invasive aortic valve replacement reduces surgical trauma and, supposedly, postoperative pain, blood loss, and length of stay. A prospective, randomized study was designed to prove these theoretical advantages.

Forty patients undergoing isolated, elective aortic valve replacement were randomized into two equal groups. Patients in group M underwent aortic valve replacement through a ministernotomy (reversed L or reversed C). In group S, a median sternotomy was used. The anesthetic and surgical protocol was identical for both groups. Pain was evaluated on a daily basis. Pulmonary function tests were performed preoperatively and before hospital discharge in all patients.

There were two deaths in each group. Cross-clamp time was longer in group M: 70 +/- 19 minutes versus 51 +/- 13 minutes in group S (p = 0.005). There were no statistically significant differences between groups M and S in pump time (95 +/- 20 minutes versus 83 +/- 19 minutes), extubation time (9.9 hours in both groups), chest drainage (479 +/- 274 mL/L 24 hours versus 355 +/- 159 mL/24 hours), transfusion requirements (27% in both groups), pain evaluation (1.34 +/- 1.3 versus 2.15 +/- 1.5), length of stay (6.2 +/- 2.3 days versus 6.3 +/- 2.5 days), and cosmetic appraisal. Forced vital capacity decreased 26% from preoperative reference values in group M and 33% in group S (p = not significant). Forced expiratory volume in 1 second decreased 22% and 35%, respectively (p = not significant).

This study has failed to prove the theoretical advantages of minimally invasive aortic valve replacement. With this technique, cross-clamp time is longer than with a median sternotomy.

Does ministernotomy improve postoperative outcome in aortic valve operation? A prospective randomized study.

Abstract:
The aim of this study was to compare the postoperative outcome obtained in patients undergoing elective aortic valve operation, either through ministernotomy or conventional sternotomy.

Between January 1999 and July 2001, 80 consecutive patients undergoing elective aortic valve replacement were randomly divided into two groups: group I (n = 40 patients) undergoing a ministernotomy approach (reversed-C or reversed-L), and group II (n = 40 patients) undergoing conventional sternotomy.

The length of skin incision was significantly shorter in group I than in group II (8.2+/-1.3 cm versus 23.7+/-2.6 cm, p < 0.001). No significant differences were found in cardiopulmonary bypass duration, associated procedures, or aortic cross-clamping times. Total operating time was 3.7+/-0.46 hours in group I compared with 3.4+/-0.6 hours in group II (p = 0.014). A similar incidence of cardiac, neurologic, infective, and renal complications between groups was found. Mean mediastinal drainage and mean blood transfusions (amount of blood transfused) per patient were greater in group II (p < 0.004 and p < 0.001, respectively). Twenty-five (62.5%) patients in group II and 15 (37.5%) patients in group I required postoperative blood transfusion (p = 0.04). Mechanical ventilation time was significantly longer in group II (6.2+/-1.8 hours versus 4.4+/-0.9 hours, p = 0.006). Five days after the surgical procedure, spirometric data analysis demonstrated a significantly lower total lung capacity and maximum inspiratory and expiratory pressures in group II compared with group I (p = 0.003, p = 0.007, and p < 0.001, respectively).

Our results showed that ministernotomy had not only important cosmetic advantages but also beneficial effects in blood loss and transfusion, postoperative pain, and probably in sternal stability. Ministernotomy also improved recovery of respiratory function and allowed earlier extubation and hospital discharge.

Pain and quality of life after minimally invasive versus conventional cardiac surgery.

Abstract:
The aim of this study was to evaluate pain and quality of life after minimally invasive cardiac operations in comparison with conventional cardiac operations.

From October 1996 to May 1997 a total of 338 patients were interviewed daily using standard scoring systems (myocardial revascularization, n = 160; mitral valve reconstruction or replacement, n = 58; aortic valve replacement, n = 120).

Regarding ventricular function and intensive care and hospital stay, there were no significant differences between groups. Pain decreased until the seventh postoperative day in all patients. Patients with a lateral minithoracotomy (minimally invasive revascularization and mitral valve operations) had lower pain levels from the third postoperative day onward. There were no differences in quality of life, postoperative wound healing, or stability of the bony thorax.

In cardiac operations overall pain levels are relatively low. After minimally invasive procedures with lateral minithoracotomy, earlier mobilization is possible because of a better stability of the bony thorax, resulting in lower pain levels.

"I" ministernotomy for aortic valve replacement.

Abstract:
Minimally invasive surgical approaches have been applied recently in the management of valvular heart disease. In this report, we reviewed our preliminary experience of minimally invasive aortic valve replacement.

Eighteen patients were operated on by means of an "I" ministernotomy, and 16 patients were operated on by means of a full median sternotomy during the same period. There was no difference between these two groups in term of age, sex, and preoperative left ventricular ejection fraction. In patients of the ministernotomy group, the operations were approached through an "I" median sternal split, from the second to the fifth intercostal space, 8 to 10 cm in length, with transverse division. Cardiopulmonary bypass was established through aorto-right atrial cannulation with aortic cross-clamping and antegrade or retrograde delivery of blood cardioplegia.

Under direct vision, aortic valve replacement was performed successfully in patients of both groups. The duration of cardiopulmonary bypass time and aortic cross-clamp time was significantly longer in the ministernotomy group than in the full sternotomy group. However, the length of incision, duration of endotracheal intubation, intensive care unit stay, pain score, postoperative length of stay, and return to normal activity interval were significantly shorter and lower in patients of the ministernotomy group than in those of the full sternotomy group. All patients recovered from the operation rapidly. Follow-up was complete in all patients with no late complications. Echocardiographic examination showed good function of aortic prostheses.

Our experience demonstrates that the "I" ministernotomy provides good exposure, reduced wound pain, enhanced recovery, shortened hospital stay, and good cosmetic healing. It may be a good alternative for surgical correction of aortic valve lesions.

Minimally invasive aortic valve replacement (AVR) compared to standard AVR.

Abstract:
Minimally invasive cardiac surgery has been developed to offer patients the benefits of open heart operations with decreased pain and limited skin incision. A limited superior median sternotomy has been shown to provide a good exposure for aortic valve replacement (AVR) and good results. In this study we report the results of minimally invasive AVR compared to standard sternotomy AVR performed in the same period.

From May 1996 to January 1998, 86 patients received isolated aortic valve replacement by the limited superior median sternotomy(group 1). As a control group (group 2), 78 patients were enrolled who underwent isolated aortic valve replacements by standard sternotomy in the same period.

Median ischemic time and median bypass time between the two groups showed no significant difference (P > 0.05). Median entire operation time in group 1 was obviously shorter than that in group 2 (P < 0.01). Median postoperative drainage was 229 ml in group 1, 369 ml in group 2. The difference between the two groups (P < 0.05) was significant. Median postoperative respiratory support time was 7.43 h in group 1, 11.26 h in group 2, with significant difference (P < 0.05). Median duration of hospital stay were 6.2 days in group 1, 9.4 days in group 2, with significant difference (P < 0.01). Reoperations for bleeding were two in group 1, four in group 2, superficial wound infection and sternum disruption occurred once in group 1 and four times in group 2. There were two hospital deaths respectively in the two groups (not procedure related).

The limited superior median sternotomy provides good exposure to the left ventricular outflow tract, aortic valve, ascending aorta, and even to the mitral valve through the roof of the left atrium. Therefore it seems to be suitable for all kinds of aortic valve operations. Besides less pain, shorter skin incision, shorter respiratory support time and lower blood loss, it has more advantages as opening and closure of the sternum is faster; decreasing infection and disruption of the sternum, and finally decreasing the time required for hospitalization and recovery.

Pulmonary function following aortic valve replacement: a comparison between ministernotomy and median sternotomy.

Abstract:
Minimally invasive aortic valve replacement (AVR) has several theoretical advantages over standard median sternotomy, but the effects of these techniques on postoperative pulmonary function have not been determined.

Twenty-six patients undergoing AVR through either a ministernotomy (group M; n = 12) or a median sternotomy (group S; n = 14) underwent pulmonary function tests. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), PaO2 and PaCO2 were determined preoperatively and before hospital discharge (at a mean of five days). Data regarding time to extubation, degree of pain and opening of the pleura were collected prospectively. Both groups had similar preoperative characteristics.

There was a significant decrease in FVC, FEVJ, PaO2 and PaCO2 during the postoperative period in all patients, though differences between the groups were not significant. Patients in group M referred less pain than those in group S. In this group, the fall in FVC and FEV1 correlated with the degree of pain, while preoperative FVC correlated with early extubation. Pleurotomy did not affect pulmonary function or pain.

FVC, FEV1, PaO2 and PaCO2 are reduced significantly following AVR, but a minimally invasive approach does not prevent postoperative pulmonary dysfunction.

Aortic valve replacement via ministernotomy: early results of a two-center study.

Abstract:
The reversed T ministernotomy has been proposed by Gundry to perform different congenital and common acquired heart valve operations. In this study we assessed the technical aspects of this approach for aortic valve replacement before starting a prospective randomized study. We evaluated the results of a two-Center study on the technical feasibility of aortic valve replacement via the reversed T ministernotomy according to the Gundry's approach.

From January to October 1998 aortic valve replacement via ministernotomy was successfully accomplished in 16 patients at the Catholic University of the Sacred Heart of Rome (Italy) and the Academisch Ziekenhuis of Groningen (The Netherlands).

No complications were reported, except for the damage to the internal mammary artery during the opening of the sternum. The mean postoperative stay was 5.1 days. The postoperative respiratory recovery was easy and fast.

Prospective randomized studies are needed to evaluate the effectiveness of the minimally invasive approach compared to standard sternotomy.

Minimally-invasive versus conventional aortic valve replacement--perioperative course and mid-term results.

Abstract:
We performed a case-control-study to compare perioperative and mid-term results of minimally invasive with conventional aortic valve replacement.

Between 8/96 and 7/97, 113 patients underwent isolated aortic valve replacement (minimally invasive: 29, conventional: 84) in our Department. Diagnosis, ejection fraction, pressure gradient/regurgitation fraction, age, gender and body-mass-index were used as matching criteria for the case-control-study. For qualitative data correspondence was requested, for quantitative data deviations up to 10% were accepted. With these criteria 25 patients of the minimally invasive group were matched to 25 patients of conventional group. All patients were reexplored 1 year after aortic valve replacement. Statistical analysis was done by the Fisher's exact test for qualitative data and the Mann-Whitney test for quantitative data.

We implanted 15 (20) bioprosthesis' and 10 (five) mechanical prosthesis' in the minimally invasive, respectively, conventional group. There were no statistically significant differences between both groups with respect to the perioperative course, only duration of surgery (mean 201.6 vs. 143.9 min, P < 0.01) and extracorporeal circulation (mean 116.1 vs. 71.3 min, P < 0.01) as well as aortic-cross-clamp-time (mean 77.9 vs. 46.9 min, P < 0.01) were significantly longer in the minimally invasive group. Postoperative complications occurred in one patient of the minimally invasive group (dissection of the right coronary artery) and four patients of the conventional group (third degree AV block, pneumothorax, grand mal convulsion, cardiopulmonary resuscitation). Two patients, one of each group, died during follow-up for unknown reasons. Follow-up revealed no significant differences with respect to clinical and echocardiographic data, but the shorter skin incision was cosmetically more accepted by patients of the minimally invasive group. Minor paravalvular leaks occurred in four patients of the minimally invasive and three patients of the conventional group as diagnosed by transthoracic echocardiography.

Both surgical techniques may be performed with comparable perioperative and mid-term results, but the better cosmetic result in the minimally invasive group is paid by a longer duration of surgery.

Stress caused by minimally invasive cardiac surgery versus conventional cardiac surgery: incidence of systemic inflammatory response syndrome.

Abstract: The present study was conducted to evaluate the degree of stress in patients induced by minimally invasive cardiac surgery (MICS) in comparison with that caused by conventional cardiac surgery. We did this by assessing the incidence of systemic inflammatory response syndrome (SIRS). A total of 48 adult patients who underwent surgery for single valve disease were included in this study, 27 of whom underwent conventional surgery and 21 MICS. We evaluated the stress inflicted on the patients in these two groups by analyzing the duration and degree of SIRS and the level of C-reactive protein (CRP). SIRS was assessed by measuring body temperature, heart rate, respiratory rate, and white blood cell counts. There were no significant differences in the operating times, perfusion times, or aorta clamp times between the two groups; and the mean volume of blood transfusion did not differ significantly either. There was no significant difference in the incidence of SIRS or the mean duration of SIRS between the two groups. The CRP levels did not differ significantly between the two groups. Thus although MICS is superior to conventional cardiac surgery in that only a small skin incision is required, the stress experienced by the patient may be the same as that experienced by the patient undergoing conventional cardiac surgery.


Context: Management of chronic obstructive pulmonary disease (COPD) commonly involves a combination of long-acting bronchodilators including beta2-agonists (LABA) and muscarinic antagonists (LAMA). LABA and LAMA bronchodilators are now available in single-combination inhalers. In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used with combination LABA and LAMA inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers as a triple therapy remain unclear.

To assess the effects of adding an ICS to combination LABA/LAMA inhalers for the treatment of stable COPD.

We included parallel-group randomised controlled trials of three weeks' duration or longer that compared the treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone.

Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial.

Abstract:
Inhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease (COPD), but the potential benefits of their use in triple therapy are not well known. We aimed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD, without a requirement for a history of exacerbations.

In this double-blind, parallel-group, multicentre phase 3 randomised controlled trial, we recruited patients from hospitals and care centres in Canada, China, Japan, and the USA. Eligible patients were 40-80 years of age, were current or former smokers (with a smoking history of ≥10 pack-years), had an established clinical history of COPD, and were symptomatic for COPD, despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening. We randomly assigned patients (2:2:1:1) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 μg (BGF MDI), glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 μg (GFF MDI), budesonide/formoterol fumarate metered-dose inhaler 320/9·6 μg (BFF MDI), or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 μg (BUD/ FORM DPI). Primary endpoints for the Europe/Canada statistical analysis approach were FEV

Between Aug 20, 2015, and Jan 5, 2018, 3047 patients were screened from 215 sites, and 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319). Over 24 weeks, BGF MDI significantly improved FEV

BGF MDI was efficacious, well tolerated, and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history.

Pearl-a member of the AstraZeneca Group.

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD.

Abstract:
The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β

In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium-vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment.

The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001).

Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).

A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol.

Abstract: Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017.

Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial.

Abstract:
Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β

This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 μg/43 μg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 μg/5 μg/9 μg) twice per day or one inhalation of IND/GLY (85 μg/43 μg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850.

Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45-0·57) for BDP/FF/G and 0·59 per patient per year (0·53-0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723-0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY.

In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia.

Chiesi Farmaceutici.

A phase III study of triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 320/18/9.6 μg and 160/18/9.6 μg using co-suspension delivery technology in moderate-to-very severe COPD: The ETHOS study protocol.

Abstract:
Single inhaler triple therapies providing an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting β

ETHOS is an ongoing, randomized, double-blind, multicenter, parallel-group, 52-week study in symptomatic patients with moderate-to-very severe COPD and a history of exacerbation(s) in the previous year. Two doses of single inhaler triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI 320/18/9.6 μg and 160/18/9.6 μg) will be compared to glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg and budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, all formulated using co-suspension delivery technology. Outcomes include the rate of moderate/severe (primary endpoint) and severe COPD exacerbations, symptoms, quality of life, and all-cause mortality. Sub-studies will assess lung function and cardiovascular safety.

From June 2015-July 2018, 16,044 patients were screened and 8572 were randomized. Preliminary baseline demographics show that 55.9% of patients had experienced ≥2 moderate/severe exacerbations in the previous year, 79.1% were receiving an ICS-containing treatment at study entry, and 59.9% had blood eosinophil counts ≥150 cells/mm

ETHOS will provide data on exacerbations, patient-reported outcomes, mortality, and safety in 8572 patients with moderate-to-very severe COPD receiving triple and dual fixed-dose combinations. For the first time, ICS/LAMA/LABA triple therapy with two different doses of ICS will be compared to dual ICS/LABA and LAMA/LABA therapies.

NCT02465567.

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD.

Abstract:
#BACKGROUND: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β
#METHODS: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only.
#RESULTS: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group.
#CONCLUSIONS: Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).


Context: Immunisation plays a major role in reducing childhood morbidity and mortality. Getting children immunised against potentially fatal and debilitating vaccine-preventable diseases remains a challenge despite the availability of efficacious vaccines, particularly in low- and middle-income countries. With the introduction of new vaccines, this becomes increasingly difficult. There is therefore a current need to synthesise the available evidence on the strategies used to bridge this gap. This is a second update of the Cochrane Review first published in 2011 and updated in 2016, and it focuses on interventions for improving childhood immunisation coverage in low- and middle-income countries.

To evaluate the effectiveness of intervention strategies to boost demand and supply of childhood vaccines, and sustain high childhood immunisation coverage in low- and middle-income countries.

Eligible studies were randomised controlled trials (RCTs), non-randomised RCTs (nRCTs), controlled before-after studies, and interrupted time series conducted in low- and middle-income countries involving children that were under five years of age, caregivers, and healthcare providers.

Home delivery of heat-stable vaccines in Indonesia: outreach immunization with a prefilled, single-use injection device.

Abstract:
Extending immunization coverage to underserved populations will require innovative immunization strategies. This study evaluated one such strategy: the use of a prefilled, single-use injection device for outreach immunization by village midwives. The device, UniJect, is designed to prevent refilling or reuse. Stored at ambient temperatures for up to 1 month in midwives' homes, vaccine-filled UniJect devices were immediately available for outreach. Between July 1995 and April 1996, 110 midwives on the Indonesia islands of Lombok and Bali visited the homes of newborn infants to deliver hepatitis B vaccine to the infants and tetanus toxoid to their mothers. Observations and interviews showed that the midwives used the device properly and safely to administer approximately 10,000 sterile injections in home settings. There were no problems with excessive heat exposure during the storage or delivery of vaccine. Injection recipients and midwives expressed a strong preference for the UniJect device over a standard syringe. Use of the prefilled device outside the cold chain simplified the logistics and facilitated the speed and efficiency of home visits, while the single-dose format minimized vaccine wastage.

Recent studies have found that up to 30% of injections given for immunization are not sterile.  Disposable syringes are reused and reusable syringes are often improperly sterilized.  Findings are presented from an evaluation of the use of a prefilled, single-use injection device for outreach immunization by village midwives.  Such devices can reduce the transmission of bloodborne pathogens and diseases, and reduce vaccine wastage associated with multi-dose vials.  The device evaluated, UniJect, is designed to prevent refilling or reuse.  Stored at ambient temperatures for up to 1 month in midwives' homes, vaccine-filled UniJect devices were immediately available for use.  Between July 1995 and April 1996, 110 midwives on the Indonesian islands of Lombok and Bali visited the homes of newborn infants to deliver hepatitis B vaccine to infants and tetanus toxoid to their mothers.  Observations and interviews found that the midwives safely and properly used the device to administer approximately 10,000 sterile injections in home settings.  No problems were experienced with excessive heat exposure during the storage or delivery of vaccine.  Injection recipients and midwives strongly preferred the UniJect device over a standard syringe.  Furthermore, use of the prefilled device outside of the cold chain simplified the logistics and facilitated the speed and efficiency of home visits, while the single-dose format minimized vaccine wastage.

The improvement of immunization coverage by early immunisation of children in Malaysia.

[Investigation on the effect and strategy of polio eradication in Hainan Province].

Abstract:
Hainan Province was a hyperendemic area of poliomyelitis, with an average incidence rate of 0.28 per hundred thousand before 1993. A series of strategy was developed for polio eradication in the whole province in July 1993.

Health education, regular and strenthening immunization programs, AFP surveillance.

1. OPV vaccination rate increased to 97.93%, 2. incidence rate of polio had a 80.93% reduction, 3. seasonal peak of epidemic was cut down, 4. endemic cycle was broken and 5. the endemic area became smaller. The number of counties (cities) where polio cases occured reduced for 81.33% in 1993 than that in 1989. Four boosters had been implemented from 1993 to 1997, to eliminated blank spots of immunization. The average geometric antibody of titre increased to 1:400 and above. After the establishment of polio surveillance system in 1991, 1. the reporting rate of non-AFP increased from 0 to 1.27 per hundred thousand, 2. rate of double specimens collection increased from 0 to 87.10%, 3. positive rate of virus isolation from 23.07% to 34.80%, 4. the positive specimens were appraised by National Polio Surveillance Center and no wild strain was found. Health education has made remarkable impact and immunization knowledge among parents had a 75 percentage point increase.

Results showed that strategy of polio eradication has made positive effects and provided valuable experiences for the control or elimination of diseases which can be prevented by vaccines.

The hepatitis B prevention education programme in Poland.

Abstract: The main objective of the hepatitis B prevention education programme in Poland is to promote education in the school setting. The programme stems from the national policy for the prevention of hepatitis B virus (HBV) infection and is an element of the national Health Prevention Programme. The main aims of the programme include reducing morbidity from HBV infection by increasing community awareness, facilitating access to vaccination, establishing local lobbies to support the programme, and encouraging cooperation with vaccine producers. The education programme has been implemented in three phases, starting with a pilot programme in 1996 that was extended to half of Poland in 1997 and to the whole country in 1998. The programme is divided into five stages, consisting of meetings at central, voivodship and local levels, vaccination of children and evaluation of the programme.

Evaluation of the hepatitis B prevention education programme in Poland.

Abstract: Evaluation of the hepatitis B prevention education programme was performed as a survey including all the coordinators in 25 regions (211 coordinators; half the country). The success of the programme was defined by an objective measure (the ratio of vaccinated children to the total number of children in a region) and a subjective measure (the need to introduce changes in current procedures). The best information was felt to be provided on the subjective area, with financial aspects raising the most doubts. There was a high level of participation in local training by school nurses, but insufficient participation by paediatric nurses and paediatricians. In one-third of the regions schools fulfilled the tasks set them, but in 19% of the regions only a few schools did. Information about vaccination was given in most public children's clinics in 65% of the regions, but there was no activity in 6% of the regions. Recruitment of sponsorship was successful, with only 12% of parents paying the full cost of vaccination. The most important factors contributing to the success of the education programme were the health education and the epidemiology departments of state sanitary inspection, the schools' medical services and paediatric services. The greatest perceived need for change in procedures was in the area of cooperation with local authorities. Only 56% of those surveyed felt the director of the local sanitary station participated to a significant extent, though the programme is very dependent on such participation. Overall, 12% of the regions achieved a ratio of 20 or more between vaccinated and non-vaccinated children, with another 52% reaching a ratio of 5-19.9. The perceived need for changes in cooperation with the Health Service was smaller in regions in which the ratio of vaccinated children was higher. The survey showed a connection between the results of the education programme and the incidence of hepatitis B virus infection.

Awareness of pulse polio immunisation.

Abstract: Mass polio immunisation campaign was launched in the national capital territory of Delhi with 2 doses of polio vaccine to be administered to children upto 3 years of age on October and December 4, 1994 respectively. Massive information, education & communication (IEC) efforts through mass media and interpersonal communication preceded the dates of the campaign. A study to assess the awareness of general population was carried out by interviewing 225 adult residents of Delhi using a structured questionnaire. These were drawn by two stage stratified random sampling. Zonewise assembly segments in the first stage and census enumeration blocks in the second stage formed the sampling frame. The study, carried out 3 days prior to date of administration of first dose of oral polio, revealed that 60.4% of population was aware of the programme being launched and 31.6% about aim of the programme. None of the respondents were aware of all the specific parameters put together correctly viz., objective, immunisation days, age group & immunisation status of children. The higher level of awareness was directly proportional to the level of education. The overwhelming success of the programme was indicated by immunisation of > 90% children upto 3 years of age all over Delhi in the first phase of the programme. The key to success of the programme despite low awareness is explained on the basis of unflinching efforts put in by vaccine centre level committees, integrated child development scheme (ICDS) and urban basic service (UBS) functionaries in mobilising people to reach various vaccination centres. Other states planning to launch such mass campaigns should pay attention to social mobilisation in addition to IEC efforts for successful completion of the programme.

Evaluation of mass pulse immunization with oral polio vaccine in Delhi: is pre-registration of children necessary?

Abstract: Delhi was the fourth State in India to conduct mass immunization of children (Pulse Polio Immunization) of the < 3 year age group with Oral Polio Vaccine (OPV) as a strategy towards the eradication of poliomyelitis. This study attempted to evaluate the immunization coverage achieved and the channels of communication which were effective in increasing coverage in three high risk areas of Delhi during October 1994. The overall immunization coverage was 89%. Information sources like enumeration visits, posters, television, radio and schools statistically correlated with the Pulse Polio Immunization (PPI) outcome. However, the cost of enumeration was high. Other less expensive channels of communication appeared to be equally effective. Only 11% of the children surveyed were not immunized with PPI OPV. The major reasons why some children did not receive OPV was that parents were "not informed" or they were "too busy".

Improving immunization coverage in rural areas of Ecuador: a cost-effectiveness analysis.

Abstract: This study describes the costs and outcomes of two different immunization strategies used by the district level of the Ministry of Health carried out between 1993 and 1995 in Low-Napo area, Napo, Ecuador. One was centrally planned and managed by the District Hospital (DH) and the other planned and implemented together with community health workers (CHW). Immunization costs were estimated directly from survey records and communication of the Ministry of Health. Outcomes information was abstracted from the vaccination statistics of the Napo Province Health Department for 1993/1995. Community health workers strategy immunized 113 children with an average cost of US $32 per child. District Hospital strategy had an average cost of US $777.6 per immunized child.Thus, CHWs strategy is more effective and less costly than the DH strategy. This study shows that in order to maximize the cost-effectiveness of immunization, it is important to involve community participation in both planning and implementation. Continuous follow-up and evaluation of the immunization programme and further research on vaccine efficacy are necessary in order to maintain these results.

Low-cost on-the-job peer training of nurses improved immunization coverage in Indonesia.

Abstract: In Indonesia responsibility for immunizations is placed on local government health centres and on the nurses who provide the immunizations at each centre. An on-the-job peer training programme for these nurses, which was designed to improve the immunization performance of poorly performing health centres in terms of coverage and practice in Maluku province, was evaluated. Experienced immunization nurses were sent to health centres where nurses were inexperienced or performing poorly; the experienced nurses spent 1-2 weeks providing on-the-job training for the less experienced ones. An evaluation of the 13 centres that participated in the programme and the 95 that did not found that the programme increased both immunization coverage and the quality of practice. Coverage of diphtheria/pertussis/tetanus (DPT), polio, and measles vaccinations rose by about 39% in all 13 participating centres when compared with non-participating centres, and by about 54% in the 11 centres that had a functioning transportation system during the year after training. These results reflect increases in the actual number of doses given and improvements in the accuracy of reports. Potential threats to the study's validity were examined and found not to be significant. The out-of-pocket cost of the training programme was about US$ 53 per trainee or about US$ 0.05 per additional vaccine reported to have been given. The marginal cost per additional fully immunized child was estimated to be US$ 0.50.

Changes in Expanded Program for Immunization coverage for mother and child in Krakor, Cambodia 1996--1998.

Abstract: We evaluated a training intervention aimed at enhancing the roles of health centre staff, Village Health Volunteers (VHVs) and Traditional Birth Attendants (TBAs) within the Expanded Program for Immunization (EPI) in the district of Krakor, Cambodia. We conducted population-based surveys to determine the coverage of the EPI at baseline (1996) and after the intervention (1998), using data from health cards for mothers and their children and history data. Statistically significant changes over the 2-year period were apparent for tetanus, BCG, polio and DTP, supporting the positive impact the training intervention had on immunization coverage in the district.