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A Randomized, Controlled Trial of Liraglutide for Adolescents With Obesity

Author/s: 
Kelly, AS, Auerbach, P, Barrientos-Perez, M, Gies, I, Hale, PM, Marcus, C, Mastrandrea, LD, Prabhu, N, Arslanian, S, NN8022-4180 Trial Investigators

Background: Obesity is a chronic disease with limited treatment options in pediatric patients. Liraglutide may be useful for weight management in adolescents with obesity.

Methods: In this randomized, double-blind trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we enrolled adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Participants were randomly assigned (1:1) to receive either liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary end point was the change from baseline in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) standard-deviation score at week 56.

Results: A total of 125 participants were assigned to the liraglutide group and 126 to the placebo group. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56 (estimated difference, -0.22; 95% confidence interval [CI], -0.37 to -0.08; P = 0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants in the liraglutide group and in 20 of 105 participants in the placebo group (estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). A greater reduction was observed with liraglutide than with placebo for BMI (estimated difference, -4.64 percentage points) and for body weight (estimated difference, -4.50 kg [for absolute change] and -5.01 percentage points [for relative change]). After discontinuation, a greater increase in the BMI standard-deviation score was observed with liraglutide than with placebo (estimated difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment.

Conclusions: In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy. (Funded by Novo Nordisk; NN8022-4180 ClinicalTrials.gov number, NCT02918279.).

Keywords 
obesity children adolscent body mass index body weight weight loss

A Randomized, Controlled Trial of Liraglutide for Adolescents With Obesity

Author/s: 
Kelly, A.S., Auerbach, P., Barrientos-Perez, M., Gies, I., Hale, P.M., Marcus, C., Mastrandrea, L.D., Prabhu, N., Arslanian, S.

Background: Obesity is a chronic disease with limited treatment options in pediatric patients. Liraglutide may be useful for weight management in adolescents with obesity.

Methods: In this randomized, double-blind trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we enrolled adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Participants were randomly assigned (1:1) to receive either liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary end point was the change from baseline in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) standard-deviation score at week 56.

Results: A total of 125 participants were assigned to the liraglutide group and 126 to the placebo group. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56 (estimated difference, -0.22; 95% confidence interval [CI], -0.37 to -0.08; P = 0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants in the liraglutide group and in 20 of 105 participants in the placebo group (estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). A greater reduction was observed with liraglutide than with placebo for BMI (estimated difference, -4.64 percentage points) and for body weight (estimated difference, -4.50 kg [for absolute change] and -5.01 percentage points [for relative change]). After discontinuation, a greater increase in the BMI standard-deviation score was observed with liraglutide than with placebo (estimated difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment.

Conclusions: In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy. (Funded by Novo Nordisk; NN8022-4180 ClinicalTrials.gov number, NCT02918279.).

Aspirin for Primary Atherosclerotic Cardiovascular Disease Prevention as Baseline Risk Increases: A Meta-Regression Analysis

Author/s: 
Nudy, M, Cooper, J, Ghahramani, M, Ruzieh, M, Mandrola, J, Foy, AJ

Background

Aspirin is often prescribed for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) however, recent randomized trials (RCTs) have challenged this practice. Despite this, aspirin is commonly recommended for high risk primary prevention. We tested the hypothesis that aspirin is more efficacious for the primary prevention of ASCVD, as the baseline risk increases.

Methods

RCTs that compared aspirin to control for primary prevention and evaluated ASCVD (composite of myocardial infarction and ischemic stroke) and major bleeding were included. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. A regression analysis was performed using the ASCVD event rate in the control arm of each RCT as the moderator.

Results

Twelve RCTs were identified with 963,829 patient years of follow-up. Aspirin was associated with a reduction in ASCVD (4.7 versus 5.3 events per 1,000 patient years; RR 0.86; 95% CI 0.79-0.92). There was increased major bleeding among aspirin users (2.5 versus 1.8 events per 1000 patient years, RR 1.41 95% CI, 1.29-1.54). Regression analysis found no relationship between the log rate ratio of ASCVD or major bleeding and incidence of ASCVD in the control arm of each RCT.

Conclusion

Aspirin is associated with a reduction in ASCVD when used for primary prevention; however, it is unlikely to be clinically significant given the increase in bleeding. More importantly, aspirin's treatment effect does not increase as ASCVD risk increases as many hypothesize. There is no suggestion from this data that use of aspirin for higher risk primary prevention patients is beneficial.

Keywords 
aspirin primary prevention Atherosclerotic Cardiovascular Disease myocardial infarction Ischemic Stroke Major Bleeding

Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review Update. Comparative Effectiveness Review No. 227

Author/s: 
Skelly, AC, Chou, R, Dettori, JR, Turner, JA, Friedly, JL, Rundell, SD, Fu, Brodt, ED, Wasson, N, Kantner, S, Ferguson, AJR

Objectives. We updated the evidence from our 2018 report assessing persistent improvement in outcomes following completion of therapy for noninvasive nonpharmacological treatment for selected chronic pain conditions.

Data sources. Electronic databases (Ovid MEDLINE®, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews) through November 2017 (for prior report) and from September 2017 through September 2019 (for this update report), reference lists, ClinicalTrials.gov, and our previous report.

Review methods. Using predefined criteria, we selected randomized controlled trials (RCTs) of noninvasive nonpharmacological treatments for five common chronic pain conditions (chronic low back pain; chronic neck pain; osteoarthritis of the knee, hip, or hand; fibromyalgia; and tension headache) that reported results for a at least 1 month postintervention. We analyzed effects and assessed strength of evidence (SOE) at short term (1 to <6 months following treatment completion), intermediate term (≥6 to <12 months), and long term (≥12 months).

Results. We included 233 RCTs (31 new to this update). Many were small (N<70), and evidence beyond 12 months after treatment completion was sparse. The most common comparison was with usual care. Evidence on harms was limited, with no evidence suggesting increased risk for serious treatment-related harms for any intervention. Effect sizes were generally small for function and pain.

Chronic low back pain: Psychological therapies were associated with small improvements compared with usual care or an attention control for both function and pain at short-term, intermediate-term, and long-term followup (SOE: moderate). Function improved over short and/or intermediate term for exercise, low-level laser therapy, spinal manipulation, massage, yoga, acupuncture, and multidisciplinary rehabilitation (SOE moderate at short term for exercise, massage, and yoga; low for all others). Improvements in pain at short term were seen for massage, mindfulness-based stress reduction, acupuncture, and multidisciplinary rehabilitation (SOE: moderate), and exercise, low-level laser therapy, and yoga (SOE: low). At intermediate term, spinal manipulation, yoga, multidisciplinary rehabilitation (SOE: moderate) and exercise and mindfulness-based stress reduction (SOE: low) were associated with improved pain. Compared with exercise, multidisciplinary rehabilitation improved both function and pain at short and intermediate terms (small effects, SOE: moderate.)

Chronic neck pain: In the short term, low-level laser therapy (SOE: moderate) and massage (SOE: low) improved function and pain. Exercise in general improved function long term, and combination exercise improved function and pain both short and long term compared with usual care (SOE: low). Acupuncture improved function short and intermediate term, but there was no pain improvement compared with sham acupuncture (SOE: low). Compared with acetaminophen, Pilates improved both function and pain (SOE: low).

Osteoarthritis pain: Exercise resulted in small improvements in function and pain at short-term (SOE: moderate) and long-term (SOE: low), and moderate improvement at intermediate-term (SOE: low) followup for knee osteoarthritis versus nonactive comparators. Small improvements in function and pain with exercise were seen for hip osteoarthritis short term (SOE: low). Functional improvement persisted into intermediate term, but pain improvement did not (SOE: low).

Fibromyalgia: Functional improvements were seen with exercise, mind-body practices, multidisciplinary rehabilitation (SOE: low) and acupuncture (SOE: moderate) short term compared with usual care, attention control, or sham treatment. At intermediate term, there was functional improvement with exercise and acupuncture (SOE: moderate), cognitive-behavioral therapy (CBT), mindfulness-based stress reduction, myofascial release, and multidisciplinary rehabilitation (SOE: low). Long term, functional improvements persisted for multidisciplinary rehabilitation without improvement in pain (SOE: low). Compared with exercise, tai chi conferred improvement in function short and intermediate term (SOE: low). Pain was improved with exercise (short and intermediate term, SOE moderate), and for CBT (short term), mindfulness practices, and multidisciplinary rehabilitation (intermediate term) (SOE low).

Chronic tension headache: Evidence was sparse and the majority of trials were of poor quality. Spinal manipulation resulted in moderate improvement in pain short term.

Conclusions. Trials identified subsequent to the earlier report largely support previous findings—namely that exercise, multidisciplinary rehabilitation, acupuncture, CBT, mindfulness practices, massage, and mind-body practices most consistently improve function and/or pain beyond the course of therapy for specific chronic pain conditions. Additional research, including comparisons with pharmacological and other active controls, on effects beyond the immediate post-treatment period is needed, particularly for conditions other than low back pain.

Keywords 
nonpharmacological treatment chronic pain

Opioid Treatments for Chronic Pain. Comparative Effectiveness Review No. 229

Author/s: 
Chou, R, Hartung, D, Turner, J, Blazina, I, Chan, B, Levander, X, McDonagh, M, Selph, S, Fu, Pappas

Objectives. Chronic pain is common, and opioid therapy is frequently prescribed for this condition. This report updates and expands on a prior Comparative Effectiveness Review on long-term (≥1 year) effectiveness and harms of opioid therapy for chronic pain, including evidence on shorter term (1 to 12 months) outcomes.

Data sources. A prior systematic review (searches through January 2014), electronic databases (Ovid MEDLINE®, Embase®, PsycINFO®, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews through August 2019), reference lists, and clinical trials registries.

Review methods. Predefined criteria were used to select studies of patients with chronic pain prescribed opioids that addressed effectiveness or harms versus placebo, no opioid use, or nonopioid pharmacological therapies; different opioid dosing methods; or risk mitigation strategies. Effects were analyzed at short-term (1 to <6 months), intermediate-term (≥6 to <12 months), and long-term (≥12 months) followup. Studies on the accuracy of risk prediction instruments for predicting opioid use disorder or misuse were also included. Random effects meta-analysis was conducted on short-term trials of opioids versus placebo, opioids versus nonopioids, and opioids plus nonopioids versus an opioid or nonopioid alone. Magnitude of effects was classified as small, moderate, or large using predefined criteria, and strength of evidence was assessed.

Results. We included 115 randomized controlled trials (RCTs), 40 observational studies, and 7 studies of predictive accuracy; 134 were new to this update. Opioids were associated with small benefits versus placebo in short-term pain, function, and sleep quality. There was a small dose-dependent effect on pain, and effects were attenuated at longer (3 to 6 month) versus shorter (1 to 3 month) followup. Opioids were associated with increased risk of discontinuation due to adverse events, gastrointestinal adverse events, somnolence, dizziness, and pruritus versus placebo. In observational studies, opioids were associated with increased risk of an opioid abuse or dependence diagnosis, overdose, all-cause mortality, fractures, falls, and myocardial infarction versus no opioid use; there was evidence of a dose-dependent risk for all outcomes except fracture and falls.

There were no differences between opioids and nonopioid medications in pain, function, or other short-term outcomes. Opioid plus nonopioid combination therapy was associated with little improvement in pain at short-term followup versus an opioid alone. Co-prescription of benzodiazepines or gabapentinoids was associated with increased risk of overdose versus an opioid alone. No RCT evaluated intermediate- or long-term benefits of opioids versus placebo. One trial found stepped therapy starting with opioids to be associated with higher pain intensity and no difference in function or other outcomes versus stepped therapy starting with nonopioid therapy.

Limited evidence indicated no differences between long- and short-acting opioids in effectiveness, but long-acting opioids were associated with increased risk of overdose. One RCT found a taper support intervention associated with greater improvement in function but no difference in pain versus usual care.

Estimates of diagnostic accuracy for various risk prediction instruments were highly inconsistent, and there was no evidence on the effectiveness of risk mitigation strategies for improving clinical outcomes, with the exception of one study that found provision of naloxone associated with decreased emergency department visits.

Trials of patients with prescription opioid dependence found buprenorphine maintenance associated with better outcomes than buprenorphine taper and similar effects of methadone versus buprenorphine. Evidence was insufficient to evaluate benefits and harms of opioid therapy in patients at higher risk for opioid use disorder.

Conclusions. At short-term followup, for patients with chronic pain, opioids are associated with small beneficial effects versus placebo but are associated with increased risk of short-term harms and do not appear to be superior to nonopioid therapy. Evidence on intermediate-term and long-term benefits remains very limited, and additional evidence confirms an association between opioids and increased risk of serious harms that appears to be dose-dependent. Research is needed to develop accurate risk prediction instruments, determine effective risk mitigation strategies, clarify risks associated with co-prescribed medications, and identify optimal opioid tapering strategies.

Keywords 
opioid therapy chronic pain comparative review opioid-use disorder methadone Buprenorphine

Screening for Alcohol Use and Brief Counseling of Adults — 13 States and the District of Columbia, 2017

Author/s: 
McKnight-Eily, LR, Okoro, CA, Turay, K, Acero, C, Hungerford, D

What is already known about this topic?

Binge drinking increases the risk for adverse health conditions and death. Alcohol screening and brief intervention (SBI), recommended by the U.S. Preventive Services Task Force (USPSTF) for all adults in primary care, is effective in reducing binge drinking.

What is added by this report?

In 2017, 81% of survey respondents were asked by their health care provider about alcohol consumption and 38% about binge drinking at a checkup in the past 2 years. Among those asked about alcohol use and who reported current binge drinking, 80% received no advice to reduce their drinking.

What are the implications for public health practice?

Implementation of alcohol SBI as recommended by USPSTF, coupled with population-level evidence-based interventions, can reduce binge drinking among U.S. adults.

Keywords 
alcohol use screening and brief intervention alcohol SBI binge drinking

5-year mental health and eating pattern outcomes following bariatric surgery in adolescents: a prospective cohort study

Author/s: 
Järvholm, K, Bruze, G, Peltonen, M, Marcus, C, Flodmark, CE, Henfridsson, P, Beamish, AJ, Gronowitz, E, Dahlgren, J, Karlsson, J, Olbers, T

BACKGROUND:

Mental health problems are prevalent among adolescents with severe obesity, but long-term mental health outcomes after adolescent bariatric surgery are not well known. We aimed to assess mental health outcomes over 5 years of follow-up after Roux-en-Y gastric bypass surgery in adolescents who participated in the Adolescent Morbid Obesity Surgery (AMOS) study.

METHODS:

This was a non-randomised matched-control study in adolescents aged 13-18 years who had a BMI of 40 kg/m2 or higher, or 35 kg/m2 or higher in addition to obesity-related comorbidity; who had previously undergone failed comprehensive conservative treatment; and were of pubertal Tanner stage III or higher, with height growth velocity beyond peak. A contemporary control group, matched for BMI, age, and sex, who underwent conventional obesity treatment, was obtained from the Swedish Childhood Obesity Treatment Register. Data on dispensed psychiatric drugs and specialist treatment for mental disorders were retrieved from national registers with complete coverage. In the surgical group only, questionnaires were used to assess self-esteem (Rosenberg Self-Esteem [RSE] score), mood (Mood Adjective Checklist [MACL]), and eating patterns (Binge Eating Scale [BES] and Three-Factor Eating Questionnaire-R21 [TFEQ]). This study is registered with ClinicalTrials.gov (NCT00289705).

FINDINGS:

Between April 10, 2006, and May 20, 2009, 81 adolescents (53 [65%] female) underwent Roux-en-Y gastric bypass surgery, and 80 control participants received conventional treatment. The proportion of participants prescribed psychiatric drugs did not differ between groups in the years before study inclusion (pre-baseline; absolute risk difference 5% [95% CI -7 to 16], p=0·4263) or after intervention (10% [-6 to 24], p=0·2175). Treatment for mental and behavioural disorders did not differ between groups before baseline (2% [-10 to 14], p=0·7135); however, adolescents in the surgical group had more specialised psychiatric treatment in the 5 years after obesity treatment than did the control group (15% [1 to 28], p=0·0410). There were few patients who discontinued psychiatric treatment post-surgery (three [4%] receiving psychiatric drug treatment and six [7%] receiving specialised care for a mental disorder before surgery). In the surgical group, self-esteem (RSE score) was improved after 5 years (mixed model mean 21·6 [95% CI 19·9 to 23·4]) relative to baseline (18·9 [17·4 to 20·4], p=0·0059), but overall mood (MACL score) was not (2·8 [2·7 to 2·9] at 5 years vs 2·7 [2·6 to 2·8] at baseline, p=0·0737). Binge eating was improved at 5 years (9·3 [7·4 to 11·2]) relative to baseline (15·0 [13·5 to 16·5], p<0·0001). Relative changes in BMI were not associated with the presence or absence of binge eating at baseline.

INTERPRETATION:

Mental health problems persist in adolescents 5 years after bariatric surgery despite substantial weight loss. Although bariatric surgery can improve many aspects of health, alleviation of mental health problems should not be expected, and a multidisciplinary bariatric team should offer long-term mental health support after surgery.

FUNDING:

Swedish Research Council, VINNOVA, Västra Götalandsregionen, ALF VG-region, Region Stockholm, Swedish Child Diabetes Foundation, Swedish Heart and Lung Foundation, Tore Nilsson's Foundation, SUS Foundations and Donations, Capio Research Foundation, and Mary von Sydow's Foundation.

Keywords 
mental health children adolescent bariatric surgery obesity

Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder

Author/s: 
Wakeman, SE, Larochelle, MR, Ameli, O, Chaisson, CE, McPheeters, JT, Crown, WH, Azocar, F, Sanghavi, DM

IMPORTANCE:

Although clinical trials demonstrate the superior effectiveness of medication for opioid use disorder (MOUD) compared with nonpharmacologic treatment, national data on the comparative effectiveness of real-world treatment pathways are lacking.

OBJECTIVE:

To examine associations between opioid use disorder (OUD) treatment pathways and overdose and opioid-related acute care use as proxies for OUD recurrence.

DESIGN, SETTING, AND PARTICIPANTS:

This retrospective comparative effectiveness research study assessed deidentified claims from the OptumLabs Data Warehouse from individuals aged 16 years or older with OUD and commercial or Medicare Advantage coverage. Opioid use disorder was identified based on 1 or more inpatient or 2 or more outpatient claims for OUD diagnosis codes within 3 months of each other; 1 or more claims for OUD plus diagnosis codes for opioid-related overdose, injection-related infection, or inpatient detoxification or residential services; or MOUD claims between January 1, 2015, and September 30, 2017. Data analysis was performed from April 1, 2018, to June 30, 2019.

EXPOSURES:

One of 6 mutually exclusive treatment pathways, including (1) no treatment, (2) inpatient detoxification or residential services, (3) intensive behavioral health, (4) buprenorphine or methadone, (5) naltrexone, and (6) nonintensive behavioral health.

MAIN OUTCOMES AND MEASURES:

Opioid-related overdose or serious acute care use during 3 and 12 months after initial treatment.

RESULTS:

A total of 40 885 individuals with OUD (mean [SD] age, 47.73 [17.25] years; 22 172 [54.2%] male; 30 332 [74.2%] white) were identified. For OUD treatment, 24 258 (59.3%) received nonintensive behavioral health, 6455 (15.8%) received inpatient detoxification or residential services, 5123 (12.5%) received MOUD treatment with buprenorphine or methadone, 1970 (4.8%) received intensive behavioral health, and 963 (2.4%) received MOUD treatment with naltrexone. During 3-month follow-up, 707 participants (1.7%) experienced an overdose, and 773 (1.9%) had serious opioid-related acute care use. Only treatment with buprenorphine or methadone was associated with a reduced risk of overdose during 3-month (adjusted hazard ratio [AHR], 0.24; 95% CI, 0.14-0.41) and 12-month (AHR, 0.41; 95% CI, 0.31-0.55) follow-up. Treatment with buprenorphine or methadone was also associated with reduction in serious opioid-related acute care use during 3-month (AHR, 0.68; 95% CI, 0.47-0.99) and 12-month (AHR, 0.74; 95% CI, 0.58-0.95) follow-up.

CONCLUSIONS AND RELEVANCE:

Treatment with buprenorphine or methadone was associated with reductions in overdose and serious opioid-related acute care use compared with other treatments. Strategies to address the underuse of MOUD are needed.

Keywords 
opioid-use disorder treatment OUD overdose Buprenorphine methadone

Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial

Author/s: 
Cuzick, J, Sestak, I, Forbes, JF, Dowsett, M, Cawthorn, S, Mansel, RE, Loibl, S, Bonanni, B, Evans, DG, Howell, A, IBIS-II Investigators

BACKGROUND:

Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period.

METHODS:

IBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.

FINDINGS:

3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105-156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39-0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27-0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45-0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33-0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22-0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78-0·65, p<0·0001). No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69-1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo). A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57-0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.

INTERPRETATION:

This analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.

FUNDING:

Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, Sanofi Aventis, and AstraZeneca.

Keywords 
breast cancer anastrozole female
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