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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

Testosterone Treatment in Adult Men With Age-Related Low Testosterone: A Clinical Guideline From the American College of Physicians

Author/s: 
Qaseem, A., Horwitch, CA, Vijan, S, Etxeandia-Ikobaltzeta, I, Kansagara, D, Clinical Guidelines Committee of the American College of Physicians

DESCRIPTION:

The American College of Physicians (ACP) developed this guideline to provide clinical recommendations based on the current evidence of the benefits and harms of testosterone treatment in adult men with age-related low testosterone. This guideline is endorsed by the American Academy of Family Physicians.

METHODS:

The ACP Clinical Guidelines Committee based these recommendations on a systematic review on the efficacy and safety of testosterone treatment in adult men with age-related low testosterone. Clinical outcomes were evaluated by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system and included sexual function, physical function, quality of life, energy and vitality, depression, cognition, serious adverse events, major adverse cardiovascular events, and other adverse events.

TARGET AUDIENCE AND PATIENT POPULATION:

The target audience includes all clinicians, and the target patient population includes adult men with age-related low testosterone.

RECOMMENDATION 1A:

ACP suggests that clinicians discuss whether to initiate testosterone treatment in men with age-related low testosterone with sexual dysfunction who want to improve sexual function (conditional recommendation; low-certainty evidence). The discussion should include the potential benefits, harms, costs, and patient's preferences.

RECOMMENDATION 1B:

ACP suggests that clinicians should reevaluate symptoms within 12 months and periodically thereafter. Clinicians should discontinue testosterone treatment in men with age-related low testosterone with sexual dysfunction in whom there is no improvement in sexual function (conditional recommendation; low-certainty evidence).

RECOMMENDATION 1C:

ACP suggests that clinicians consider intramuscular rather than transdermal formulations when initiating testosterone treatment to improve sexual function in men with age-related low testosterone, as costs are considerably lower for the intramuscular formulation and clinical effectiveness and harms are similar.

RECOMMENDATION 2:

ACP suggests that clinicians not initiate testosterone treatment in men with age-related low testosterone to improve energy, vitality, physical function, or cognition (conditional recommendation; low-certainty evidence).

Keywords 
testosterone guidelines age-related testosterone deficiency

Association of household secondhand smoke exposure and mortality risk in patients with heart failure

Author/s: 
He, X, Zhao, J, He, J, Dong, Y, Liu, C

BACKGROUND:

Secondhand smoke (SHS) exposure is a well-established cardiovascular risk factor, yet association between SHS and prognosis of heart failure remains uncertain.

METHOD:

Data were obtained from the US National Health and Nutrition Examination Surveys III from 1988 to 1994. Currently nonsmoking adults with a self-reported history of heart failure were included. Household SHS exposure was assessed by questionnaire. Participants were followed up through December 31, 2011. Cox proportional-hazards models were used to assess the association of household SHS exposure and mortality risk. Potential confounding factors were adjusted.

RESULTS:

Of 572 currently nonsmoking patients with heart failure, 88 were exposed to household SHS while 484 were not. There were totally 475 deaths during follow-up. In univariate analysis, household SHS was not associated with mortality risk (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.76-1.26, p = 0.864). However, after adjustment for demographic variables, socioeconomic variables and medication, heart failure patients in exposed group had a 43% increase of mortality risk compared with those in unexposed group (HR: 1.43, 95% CI: 1.10-1.86, p = 0.007). Analysis with further adjustment for general health status and comorbidities yielded similar result (HR: 1.47, 95% CI: 1.13-1.92, p = 0.005).

CONCLUSION:

Household SHS exposure was associated with increased mortality risk in heart failure patients.

Keywords 
heart failure mortality secondhand smoke

Coronary Microvascular Dysfunction Causing Cardiac Ischemia in Women

Author/s: 
Wei, J, Cheng, S, Merz, CNB

Two-thirds of women who present with persistent symptoms and clinical signs of ischemia have no evidence of obstructive coronary artery disease (INOCA) on angiography. Cardiac ischemia can be manifested by chest discomfort, shortness of breath, decreased exercise tolerance, and ST-segment or imaging abnormalities at rest or with stress. Although women with a clinical presentation suggesting ischemic heart disease are often reassured after having a “normal” angiogram that their symptoms are not likely cardiac in etiology, 1 in 13 of these women die from a cardiac cause within 10 years of the angiographic evaluation, and the most frequent adverse cardiac event is hospitalization for heart failure with preserved ejection fraction with an observed 10-fold higher rate compared with asymptomatic women (3.3% vs 0.3%). For these women with INOCA, clinicians should consider the important, yet often overlooked, diagnosis of coronary microvascular dysfunction (CMD)—a small vessel disorder that confers an adverse prognosis in women for which there are available and continuously evolving diagnostic and treatment strategies.

Keywords 
coronary microvascular dysfunction CMD obstructive coronary artery disease cardiac ischemia females angina

Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial

Author/s: 
Hermida, R.C., Crespo, J.J., Domínguez-Sardiña, M, Otero, A., Moyá, A., Ríos, M.T., Sineiro, E., Castiñeira, M.C., Callejas, P.A., Pousa, L., Salgado, J.L., Durán, C., Sánchez, J.J., Fernández, J.R., Mojón, A., Ayala, D.E., Hygia Project Investigators

AIMS:

The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction.

METHODS AND RESULTS:

In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio-adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome [0.55 (95% CI 0.50-0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34-0.56)], myocardial infarction [0.66 (0.52-0.84)], coronary revascularization [0.60 (0.47-0.75)], heart failure [0.58 (0.49-0.70)], and stroke [0.51 (0.41-0.63)].

CONCLUSION:

Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events.

TRIAL REGISTRATION:

ClinicalTrials.gov, number NCT00741585.

Keywords 
antihypertensives blood pressure hypertension medication

Association between vitamin D supplementation and mortality: systematic review and meta-analysis

Author/s: 
Zhang, Y., Fang, F., Tang, J., Jia, L., Feng, Y., Xu, P., Faramand, A.

Abstract

OBJECTIVE:

To investigate whether vitamin D supplementation is associated with lower mortality in adults.

DESIGN:

Systematic review and meta-analysis of randomised controlled trials.

DATA SOURCES:

Medline, Embase, and the Cochrane Central Register from their inception to 26 December 2018.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES:

Randomised controlled trials comparing vitamin D supplementation with a placebo or no treatment for mortality were included. Independent data extraction was conducted and study quality assessed. A meta-analysis was carried out by using fixed effects and random effects models to calculate risk ratio of death in the group receiving vitamin D supplementation and the control group.

MAIN OUTCOME MEASURES:

All cause mortality.

RESULTS:

52 trials with a total of 75 454 participants were identified. Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I2=0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin D supplementation statistically significantly reduced the risk of cancer death (0.84, 0.74 to 0.95, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation (P for interaction=0.04); neither vitamin D3 nor vitamin D2 was associated with a statistically significant reduction in all cause mortality.

CONCLUSIONS:

Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 16%. Additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all cause mortality.

STUDY REGISTRATION:

PROSPERO registration number CRD42018117823.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Keywords 
cancer cancer mortality vitamin D Vitamin D3 supplimentation

Sitting Time and Risk of Cardiovascular Disease and Diabetes: A Systematic Review and Meta-Analysis.

Author/s: 
Bailey, D.P., Hewson, D.J., Champion, R.B., Sayegh, S.M.

Whether physical activity attenuates the association of total daily sitting time with cardiovascular disease and diabetes incidence is unclear. This systematic review and meta-analysis examined the association of total daily sitting time with cardiovascular disease and diabetes with and without adjustment for physical activity.

EVIDENCE ACQUISITION:

PubMed, Web of Science, BASE, MEDLINE, Academic Search Elite, and ScienceDirect were searched for prospective studies, published between January 1, 1989, and February 15, 2019, examining the association of total daily sitting time with cardiovascular disease or diabetes outcomes. Data extraction and study quality assessments were conducted by 2 independent reviewers. Pooled hazard ratios (HRs) were calculated using a fixed-effects model. The quality assessment and meta-analysis procedures were completed in 2018.

EVIDENCE SYNTHESIS:

Nine studies with 448,285 participants were included. A higher total daily sitting time was associated with a significantly increased risk of cardiovascular disease (HR=1.29, 95% CI=1.27, 1.30, p<0.001) and diabetes (HR=1.13, 95% CI=1.04, 1.22, p<0.001) incidence when not adjusted for physical activity. The increased risk for diabetes was unaffected when adjusting for physical activity (HR=1.11, 95% CI=1.01, 1.19, p<0.001). For cardiovascular disease, the increased risk was attenuated but remained significant (HR=1.14, 95% CI=1.04, 1.23, p<0.001).

CONCLUSIONS:

Higher levels of total daily sitting time are associated with an increased risk of cardiovascular disease and diabetes, independent of physical activity. Reductions in total daily sitting may be recommended in public health guidelines.

Keywords 
physical activity sitting exercise

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and
polycystic ovaries. Its etiology remains unknown, and treatment is largely symptom based and empirical. PCOS has the
potential to cause substantial metabolic sequelae, including an increased risk of diabetes and cardiovascular disease,
and these factors should be considered when determining long-term treatment. The purpose of this document is to
examine the best available evidence for the diagnosis and clinical management of PCOS.

Keywords 
polycystic ovarian syndrome

The effects of sleep extension on cardiometabolic risk factors: A systematic review

Author/s: 
Henst, R.H.P., Pienaar, P.R., Roden, L.C., Rae, D.E.

Studies have shown bidirectional relationships between short- or long-sleep duration and risk for obesity, non-communicable diseases, all-cause mortality and cardiovascular disease mortality. Increasing sleep duration may be an appropriate strategy to reduce cardiometabolic riskin short-sleeping individuals. The aim is to review the effects of sleep extension interventions on cardiometabolic risk in adults. The PubMed and Scopus databases were searched for relevant, English, peer-reviewed scientific publications (until August 2018). Seven studies that aimed to increase sleep duration in adults by any sleep extension intervention and described at least one cardiometabolic risk factor were included. These studies had a combined sample size of 138 participants who were either healthy (n = 14), healthy short-sleeping (n = 92), overweight short-sleeping (n = 10), or pre- or hypertensive short-sleeping (n = 22) individuals. The durations of the sleep extensioninterventions ranged from 3 days to 6 weeks, and all successfully increased total sleep time by between 21 and 177 min. Sleep extensionwas associated with improved direct and indirect measures of insulin sensitivity, decreased leptin and peptide tyrosine-tyrosine, and reductions in overall appetite, desire for sweet and salty foods, intake of daily free sugar, and percentage of daily caloric intake from protein. This review provides preliminary evidence for a role for sleep extension to improve cardiometabolic outcomes and directive towards future studies in the field of cardiometabolic health and sleep.

Keywords 
cardiovascular disease insulin sensitivity metabolic syndrome non-communicable diseases obese sleep duration

Cardiovascular Events and Mortality in White Coat Hypertension: A Systematic Review and Meta-analysis

Author/s: 
M.G., Cohen, J.B., Lotito, M.J., Denker, M.G., Cohen, D.L., Townsend, R.R.

BACKGROUND:

The long-term cardiovascular risk of isolated elevated office blood pressure (BP) is unclear.

PURPOSE:

To summarize the risk for cardiovascular events and all-cause mortality associated with untreated white coat hypertension (WCH) and treated white coat effect (WCE).

DATA SOURCES:

PubMed and EMBASE, without language restriction, from inception to December 2018.

STUDY SELECTION:

Observational studies with at least 3 years of follow-up evaluating the cardiovascular risk of WCH or WCE compared with normotension.

DATA EXTRACTION:

2 investigators independently extracted study data and assessed study quality.

DATA SYNTHESIS:

27 studies were included, comprising 25 786 participants with untreated WCH or treated WCE and 38 487 with normal BP followed for a mean of 3 to 19 years. Compared with normotension, untreated WCH was associated with an increased risk for cardiovascular events (hazard ratio [HR], 1.36 [95% CI, 1.03 to 2.00]), all-cause mortality (HR, 1.33 [CI, 1.07 to 1.67]), and cardiovascularmortality (HR, 2.09 [CI, 1.23 to 4.48]); the risk of WCH was attenuated in studies that included stroke in the definition of cardiovascular events(HR, 1.26 [CI, 1.00 to 1.54]). No significant association was found between treated WCE and cardiovascular events (HR, 1.12 [CI, 0.91 to 1.39]), all-cause mortality (HR, 1.11 [CI, 0.89 to 1.46]), or cardiovascular mortality (HR, 1.04 [CI, 0.65 to 1.66]). The findings persisted across several sensitivity analyses.

LIMITATION:

Paucity of studies evaluating isolated cardiac outcomes or reporting participant race/ethnicity.

CONCLUSION:

Untreated WCH, but not treated WCE, is associated with an increased risk for cardiovascular events and all-cause mortality. Out-of-office BP monitoring is critical in the diagnosis and management of hypertension.

PRIMARY FUNDING SOURCE:

National Institutes of Health.

Keywords 
blood pressure stroke cardiovascular
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