Effects of evidence-based strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme (ASCEND): four cluster-randomised controlled trials


Uptake in the national colorectal cancer screening programme in England varies by socioeconomic status. We assessed four interventions aimed at reducing this gradient, with the intention of improving the health benefits of screening.


All people eligible for screening (men and women aged 60–74 years) across England were included in four cluster-randomised trials. Randomisation was based on day of invitation. Each trial compared the standard information with the standard information plus the following supplementary interventions: trial 1 (November, 2012), a supplementary leaflet summarising the gist of the key information; trial 2 (March, 2012), a supplementary narrative leaflet describing people’s stories; trial 3 (June, 2013), general practice endorsement of the programme on the invitation letter; and trial 4 (July–August, 2013) an enhanced reminder letter with a banner that reiterated the screening offer. Socioeconomic status was defined by the Index of Multiple Deprivation score for each home address. The primary outcome was the socioeconomic status gradient in uptake across deprivation quintiles. This study is registered, number ISRCTN74121020.


As all four trials were embedded in the screening programme, loss to follow-up was minimal (less than 0·5%). Trials 1 (n=163 525) and 2 (n=150 417) showed no effects on the socioeconomic gradient of uptake or overall uptake. Trial 3 (n=265 434) showed no effect on the socioeconomic gradient but was associated with increased overall uptake (adjusted odds ratio [OR] 1·07, 95% CI 1·04–1·10, p<0·0001). In trial 4 (n=168 480) a significant interaction was seen with socioeconomic status gradient (p=0·005), with a stronger effect in the most deprived quintile (adjusted OR 1·11, 95% CI 1·04–1·20, p=0·003) than in the least deprived (1·00, 0·94–1·06, p=0·98). Overall uptake was also increased (1·07, 1·03–1·11, p=0·001).


Of four evidence-based interventions, the enhanced reminder letter reduced the socioeconomic gradient in screening uptake, but further reducing inequalities in screening uptake through written materials alone will be challenging.


National Institute for Health Research.

By Jane Wardle et al, The Lancet Volume 387, No. 10020, p751–759, 20 February 2016


Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies

Objectives To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes.

Design Systematic review and meta-analysis of randomised and observational studies.

Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts.

Eligibility criteria Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure.

Data collection and analysis Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach.

Results Eligible studies included 43 trials (n=68 775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1 777 358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15 701 v33/12 591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18 554 v 552/18 474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use.

Conclusions The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.

By Ling Li et al, BMJ 2016;352:i610

Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

Objective To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes.

Design Population based cohort.

Setting Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom.

Participants A cohort of 972 384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014.

Main outcome measures Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models.

Results During 2 024 441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking.

Conclusions In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.

By Laurent Azoulay et al, BMJ 2016;352:i581

Incidence of Dementia over Three Decades in the Framingham Heart Study


The prevalence of dementia is expected to soar as the average life expectancy increases, but recent estimates suggest that the age-specific incidence of dementia is declining in high-income countries. Temporal trends are best derived through continuous monitoring of a population over a long period with the use of consistent diagnostic criteria. We describe temporal trends in the incidence of dementia over three decades among participants in the Framingham Heart Study.


Participants in the Framingham Heart Study have been under surveillance for incident dementia since 1975. In this analysis, which included 5205 persons 60 years of age or older, we used Cox proportional-hazards models adjusted for age and sex to determine the 5-year incidence of dementia during each of four epochs. We also explored the interactions between epoch and age, sex, apolipoprotein E ε4 status, and educational level, and we examined the effects of these interactions, as well as the effects of vascular risk factors and cardiovascular disease, on temporal trends.


The 5-year age- and sex-adjusted cumulative hazard rates for dementia were 3.6 per 100 persons during the first epoch (late 1970s and early 1980s), 2.8 per 100 persons during the second epoch (late 1980s and early 1990s), 2.2 per 100 persons during the third epoch (late 1990s and early 2000s), and 2.0 per 100 persons during the fourth epoch (late 2000s and early 2010s). Relative to the incidence during the first epoch, the incidence declined by 22%, 38%, and 44% during the second, third, and fourth epochs, respectively. This risk reduction was observed only among persons who had at least a high school diploma (hazard ratio, 0.77; 95% confidence interval, 0.67 to 0.88). The prevalence of most vascular risk factors (except obesity and diabetes) and the risk of dementia associated with stroke, atrial fibrillation, or heart failure have decreased over time, but none of these trends completely explain the decrease in the incidence of dementia.


Among participants in the Framingham Heart Study, the incidence of dementia has declined over the course of three decades. The factors contributing to this decline have not been completely identified. (Funded by the National Institutes of Health.)

By Claudia L. Satizabal et al, N Engl J Med 2016; 374:523-532

Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus


Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin.


In this double-blind, placebo-controlled trial, we randomly assigned pregnant women without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of more than 35 to receive metformin, at a dose of 3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery. The BMI was calculated at the time of study entry (12 to 18 weeks of gestation). The primary outcome was a reduction in the median neonatal birth-weight z score by 0.3 SD (equivalent to a 50% reduction, from 20% to 10%, in the incidence of large-for-gestational-age neonates). Secondary outcomes included maternal gestational weight gain and the incidence of gestational diabetes and of preeclampsia, as well as the incidence of adverse neonatal outcomes. Randomization was performed with the use of computer-generated random numbers. The analysis was performed according to the intention-to-treat principle.


A total of 50 women withdrew consent during the trial, which left 202 women in the metformin group and 198 in the placebo group. There was no significant between-group difference in the median neonatal birth-weight z score (0.05 in the metformin group [interquartile range, −0.71 to 0.92] and 0.17 in the placebo group [interquartile range, −0.62 to 0.89], P=0.66). The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes.


Among women without diabetes who had a BMI of more than 35, the antenatal administration of metformin reduced maternal weight gain but not neonatal birth weight. (Funded by the Fetal Medicine Foundation; ClinicalTrials.gov number, NCT01273584; EudraCT number, 2008-005892-83.)

By Argyro Syngelaki et al, N Engl J Med 2016; 374:434-443

Weight change between successive pregnancies and risks of stillbirth and infant mortality: a nationwide cohort study


Maternal overweight and obesity are risk factors for stillbirth and infant mortality. Whether temporal changes in maternal weight affect these risks is not clear. We aimed to assess whether change of BMI between first and second pregnancies affects risks of stillbirth and infant mortality in the second-born offspring.


In a Swedish population-based cohort of women who gave birth to their first and second child between Jan 1, 1992, and Dec 31, 2012, we investigated associations between change in maternal body-mass index (BMI) during early pregnancy from first to second pregnancies and risks of stillbirth and neonatal, postneonatal, and infant mortality after the second pregnancy. Relative risks (RRs) for each outcome according to BMI change categories were calculated with binomial regression.


Complete information was available for 456 711 (77·7%) of 587 710 women who had their first and second single births in the study period. Compared with women with a stable BMI (change between −1 kg/m2 and <1 kg/m2) between pregnancies, the adjusted RRs for women who gained at least 4 BMI units between pregnancies were 1·55 (95% CI 1·23–1·96) for stillbirth and 1·29 (1·00–1·67) for infant mortality. Stillbirth risks increased linearly with increased BMI gain. Risks of infant mortality in second pregnancy only increased with BMI gain in women with healthy BMI (<25 kg/m2) during first pregnancy; the adjusted RR for healthy weight women who gained 2 to less than 4 BMI units was 1·27 (1·01–1·59) and for those who gained 4 BMI units or more the adjusted RR was 1·60 (1·16–2·22). In overweight women (BMI ≥25 kg/m2), weight loss before pregnancy reduced risk of neonatal mortality.


Our findings emphasise the need to prevent weight gain before pregnancy in healthy and overweight women and that weight loss should be promoted in overweight women.


Swedish Research Council for Health, Working Life and Welfare, and Karolinska Institutet.

By Sven Chattingius & Eduardo Villamor, The Lancet Volume 387, No. 10018, p558–565, 6 February 2016

Effect of Behavioral Interventions on Inappropriate Antibiotic Prescribing Among Primary Care Practices

Importance  Interventions based on behavioral science might reduce inappropriate antibiotic prescribing.

Objective  To assess effects of behavioral interventions and rates of inappropriate (not guideline-concordant) antibiotic prescribing during ambulatory visits for acute respiratory tract infections.

Design, Setting, and Participants  Cluster randomized clinical trial conducted among 47 primary care practices in Boston and Los Angeles. Participants were 248 enrolled clinicians randomized to receive 0, 1, 2, or 3 interventions for 18 months. All clinicians received education on antibiotic prescribing guidelines on enrollment. Interventions began between November 1, 2011, and October 1, 2012. Follow-up for the latest-starting sites ended on April 1, 2014. Adult patients with comorbidities and concomitant infections were excluded.

Interventions  Three behavioral interventions, implemented alone or in combination: suggested alternatives presented electronic order sets suggesting nonantibiotic treatments; accountable justificationprompted clinicians to enter free-text justifications for prescribing antibiotics into patients’ electronic health records; peer comparison sent emails to clinicians that compared their antibiotic prescribing rates with those of “top performers” (those with the lowest inappropriate prescribing rates).

Main Outcomes and Measures  Antibiotic prescribing rates for visits with antibiotic-inappropriate diagnoses (nonspecific upper respiratory tract infections, acute bronchitis, and influenza) from 18 months preintervention to 18 months afterward, adjusting each intervention’s effects for co-occurring interventions and preintervention trends, with random effects for practices and clinicians.

Results  There were 14 753 visits (mean patient age, 47 years; 69% women) for antibiotic-inappropriate acute respiratory tract infections during the baseline period and 16 959 visits (mean patient age, 48 years; 67% women) during the intervention period. Mean antibiotic prescribing rates decreased from 24.1% at intervention start to 13.1% at intervention month 18 (absolute difference, −11.0%) for control practices; from 22.1% to 6.1% (absolute difference, −16.0%) for suggested alternatives (difference in differences, −5.0% [95% CI, −7.8% to 0.1%]; P = .66 for differences in trajectories); from 23.2% to 5.2% (absolute difference, −18.1%) for accountable justification (difference in differences, −7.0% [95% CI, −9.1% to −2.9%]; P < .001); and from 19.9% to 3.7% (absolute difference, −16.3%) for peer comparison (difference in differences, −5.2% [95% CI, −6.9% to −1.6%]; P < .001). There were no statistically significant interactions (neither synergy nor interference) between interventions.

Conclusions and Relevance  Among primary care practices, the use of accountable justification and peer comparison as behavioral interventions resulted in lower rates of inappropriate antibiotic prescribing for acute respiratory tract infections.

Trial Registration  clinicaltrials.gov Identifier: NCT01454947

By Daniella Meeker, et al, JAMA. 2016;315(6):562-570. doi:10.1001/jama.2016.0275