Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis

Importance  The use of palliative care programs and the number of trials assessing their effectiveness have increased.

Objective  To determine the association of palliative care with quality of life (QOL), symptom burden, survival, and other outcomes for people with life-limiting illness and for their caregivers.

Data Sources  MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL to July 2016.

Study Selection  Randomized clinical trials of palliative care interventions in adults with life-limiting illness.

Data Extraction and Synthesis  Two reviewers independently extracted data. Narrative synthesis was conducted for all trials. Quality of life, symptom burden, and survival were analyzed using random-effects meta-analysis, with estimates of QOL translated to units of the Functional Assessment of Chronic Illness Therapy–palliative care scale (FACIT-Pal) instrument (range, 0-184 [worst-best]; minimal clinically important difference [MCID], 9 points); and symptom burden translated to the Edmonton Symptom Assessment Scale (ESAS) (range, 0-90 [best-worst]; MCID, 5.7 points).

Main Outcomes and Measures  Quality of life, symptom burden, survival, mood, advance care planning, site of death, health care satisfaction, resource utilization, and health care expenditures.

Results  Forty-three RCTs provided data on 12 731 patients (mean age, 67 years) and 2479 caregivers. Thirty-five trials used usual care as the control, and 14 took place in the ambulatory setting. In the meta-analysis, palliative care was associated with statistically and clinically significant improvements in patient QOL at the 1- to 3-month follow-up (standardized mean difference, 0.46; 95% CI, 0.08 to 0.83; FACIT-Pal mean difference, 11.36] and symptom burden at the 1- to 3-month follow-up (standardized mean difference, −0.66; 95% CI, −1.25 to −0.07; ESAS mean difference, −10.30). When analyses were limited to trials at low risk of bias (n = 5), the association between palliative care and QOL was attenuated but remained statistically significant (standardized mean difference, 0.20; 95% CI, 0.06 to 0.34; FACIT-Pal mean difference, 4.94), whereas the association with symptom burden was not statistically significant (standardized mean difference, −0.21; 95% CI, −0.42 to 0.00; ESAS mean difference, −3.28). There was no association between palliative care and survival (hazard ratio, 0.90; 95% CI, 0.69 to 1.17). Palliative care was associated consistently with improvements in advance care planning, patient and caregiver satisfaction, and lower health care utilization. Evidence of associations with other outcomes was mixed.

Conclusions and Relevance  In this meta-analysis, palliative care interventions were associated with improvements in patient QOL and symptom burden. Findings for caregiver outcomes were inconsistent. However, many associations were no longer significant when limited to trials at low risk of bias, and there was no significant association between palliative care and survival.

Combined associations of body weight and lifestyle factors with all cause and cause specific mortality in men and women: prospective cohort study

Objective To evaluate the combined associations of diet, physical activity, moderate alcohol consumption, and smoking with body weight on risk of all cause and cause specific mortality.

Design Longitudinal study with up to 32 years of follow-up.

Setting Nurses’ Health Study (1980-2012) and Health Professionals Follow-up Study (1986-2012).

Participants 74 582 women from the Nurses’ Health Study and 39 284 men from the Health Professionals Follow-up Study who were free from cardiovascular disease and cancer at baseline.

Main outcome measures Exposures included body mass index (BMI), score on the alternate healthy eating index, level of physical activity, smoking habits, and alcohol drinking while outcome was mortality (all cause, cardiovascular, cancer). Cox proportional hazard models were used to calculate the adjusted hazard ratios of all cause, cancer, and cardiovascular mortality with their 95% confidence intervals across categories of BMI, with 22.5-24.9 as the reference.

Results During up to 32 years of follow-up, there were 30 013 deaths (including 10 808 from cancer and 7189 from cardiovascular disease). In each of the four categories of BMI studied (18.5-22.4, 22.5-24.9, 25-29.9, ≥30), people with one or more healthy lifestyle factors had a significantly lower risk of total, cardiovascular, and cancer mortality than individuals with no low risk lifestyle factors. A combination of at least three low risk lifestyle factors and BMI between 18.5-22.4 was associated with the lowest risk of all cause (hazard ratio 0.39, 95% confidence interval 0.35 to 0.43), cancer (0.40, 0.34 to 0.47), and cardiovascular (0.37, 0.29 to 0.46) mortality, compared with those with BMI between 22.5-24.9 and none of the four low risk lifestyle factors.

Conclusion Although people with a higher BMI can have lower risk of premature mortality if they also have at least one low risk lifestyle factor, the lowest risk of premature mortality is in people in the 18.5-22.4 BMI range with high score on the alternate healthy eating index, high level of physical activity, moderate alcohol drinking, and who do not smoke. It is important to consider diet and lifestyle factors in the evaluation of the association between BMI and mortality.

Reference: BMJ 2016;355:i5855

Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis

Objectives To evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality.

Design Meta-analysis of prospective cohort studies.

Data sources Electronic databases (PubMed, Embase, and Google Scholar).

Selection criteria Prospective cohort studies from general populations were included for meta-analysis if they reported adjusted relative risks with 95% confidence intervals for associations between the risk of composite cardiovascular disease, coronary heart disease, stroke, all cause mortality, and prediabetes.

Review methods Two authors independently reviewed and selected eligible studies, based on predetermined selection criteria. Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol(5.7-6.4%) according to ADA criteria or 42-47 mmol/mol (6.0-6.4%) according to the National Institute for Health and Care Excellence (NICE) guideline. The relative risks of all cause mortality and cardiovascular events were calculated and reported with 95% confidence intervals.

Results 53 prospective cohort studies with 1 611 339 individuals were included for analysis. The median follow-up duration was 9.5 years. Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol or 42-47 mmol/mol were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.

Conclusions Prediabetes, defined as impaired glucose tolerance, impaired fasting glucose, or raised HbA1c, was associated with an increased risk of cardiovascular disease. The health risk might be increased in people with a fasting glucose concentration as low as 5.6 mmol/L or HbA1c of 39 mmol/mol.

Reference: BMJ 2016;355:i5953

Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies

Objectives To investigate the association between long term intake of individual saturated fatty acids (SFAs) and the risk of coronary heart disease, in two large cohort studies.

Design Prospective, longitudinal cohort study.

Setting Health professionals in the United States.

Participants 73 147 women in the Nurses’ Health Study (1984-2012) and 42 635 men in the Health Professionals Follow-up Study (1986-2010), who were free of major chronic diseases at baseline.

Main outcome measure Incidence of coronary heart disease (n=7035) was self-reported, and related deaths were identified by searching National Death Index or through report of next of kin or postal authority. Cases were confirmed by medical records review.

Results Mean intake of SFAs accounted for 9.0-11.3% energy intake over time, and was mainly composed of lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), and stearic acid (18:0; 8.8-10.7% energy). Intake of 12:0, 14:0, 16:0 and 18:0 were highly correlated, with Spearman correlation coefficients between 0.38 and 0.93 (all P<0.001). Comparing the highest to the lowest groups of individual SFA intakes, hazard ratios of coronary heart disease were 1.07 (95% confidence interval 0.99 to 1.15; Ptrend=0.05) for 12:0, 1.13 (1.05 to 1.22; Ptrend<0.001) for 14:0, 1.18 (1.09 to 1.27; Ptrend<0.001) for 16:0, 1.18 (1.09 to 1.28; Ptrend<0.001) for 18:0, and 1.18 (1.09 to 1.28; Ptrend<0.001) for all four SFAs combined (12:0-18:0), after multivariate adjustment of lifestyle factors and total energy intake. Hazard ratios of coronary heart disease for isocaloric replacement of 1% energy from 12:0-18:0 were 0.92 (95% confidence interval 0.89 to 0.96; P<0.001) for polyunsaturated fat, 0.95 (0.90 to 1.01; P=0.08) for monounsaturated fat, 0.94 (0.91 to 0.97; P<0.001) for whole grain carbohydrates, and 0.93 (0.89 to 0.97; P=0.001) for plant proteins. For individual SFAs, the lowest risk of coronary heart disease was observed when the most abundant SFA, 16:0, was replaced. Hazard ratios of coronary heart disease for replacing 1% energy from 16:0 were 0.88 (95% confidence interval 0.81 to 0.96; P=0.002) for polyunsaturated fat, 0.92 (0.83 to 1.02; P=0.10) for monounsaturated fat, 0.90 (0.83 to 0.97; P=0.01) for whole grain carbohydrates, and 0.89 (0.82 to 0.97; P=0.01) for plant proteins.

Conclusions Higher dietary intakes of major SFAs are associated with an increased risk of coronary heart disease. Owing to similar associations and high correlations among individual SFAs, dietary recommendations for the prevention of coronary heart disease should continue to focus on replacing total saturated fat with more healthy sources of energy.

Reference: BMJ 2016;355:i5796

Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial


Obesity is a common cause of non-communicable disease. Guidelines recommend that physicians screen and offer brief advice to motivate weight loss through referral to behavioural weight loss programmes. However, physicians rarely intervene and no trials have been done on the subject. We did this trial to establish whether physician brief intervention is acceptable and effective for reducing bodyweight in patients with obesity.


In this parallel, two-arm, randomised trial, patients who consulted 137 primary care physicians in England were screened for obesity. Individuals could be enrolled if they were aged at least 18 years, had a body-mass index of at least 30 kg/m2 (or at least 25 kg/m2 if of Asian ethnicity), and had a raised body fat percentage. At the end of the consultation, the physician randomly assigned participants (1:1) to one of two 30 s interventions. Randomisation was done via preprepared randomisation cards labelled with a code representing the allocation, which were placed in opaque sealed envelopes and given to physicians to open at the time of treatment assignment. In the active intervention, the physician offered referral to a weight management group (12 sessions of 1 h each, once per week) and, if the referral was accepted, the physician ensured the patient made an appointment and offered follow-up. In the control intervention, the physician advised the patient that their health would benefit from weight loss. The primary outcome was weight change at 12 months in the intention-to-treat population, which was assessed blinded to treatment allocation. We also assessed asked patients’ about their feelings on discussing their weight when they have visited their general practitioner for other reasons. Given the nature of the intervention, we did not anticipate any adverse events in the usual sense, so safety outcomes were not assessed. This trial is registered with the ISRCTN Registry, number ISRCTN26563137.


Between June 4, 2013, and Dec 23, 2014, we screened 8403 patients, of whom 2728 (32%) were obese. Of these obese patients, 2256 (83%) agreed to participate and 1882 were eligible, enrolled, and included in the intention-to-treat analysis, with 940 individuals in the support group and 942 individuals in the advice group. 722 (77%) individuals assigned to the support intervention agreed to attend the weight management group and 379 (40%) of these individuals attended, compared with 82 (9%) participants who were allocated the advice intervention. In the entire study population, mean weight change at 12 months was 2·43 kg with the support intervention and 1·04 kg with the advice intervention, giving an adjusted difference of 1·43 kg (95% CI 0·89–1·97). The reactions of the patients to the general practitioners’ brief interventions did not differ significantly between the study groups in terms of appropriateness (adjusted odds ratio 0·89, 95% CI 0·75–1·07, p=0·21) or helpfulness (1·05, 0·89–1·26, p=0·54); overall, four (<1%) patients thought their intervention was inappropriate and unhelpful and 1530 (81%) patients thought it was appropriate and helpful.


A behaviourally-informed, very brief, physician-delivered opportunistic intervention is acceptable to patients and an effective way to reduce population mean weight.


The UK National Prevention Research Initiative.

Community acquired pneumonia incidence before and after proton pump inhibitor prescription: population based study

Objective To examine the risk of community acquired pneumonia before and after prescription of proton pump inhibitor (PPI) and assess whether unmeasured confounding explains this association.

Design Cohort study and self controlled case series.

Setting Clinical Practice Research Datalink (1990 to 2013) in UK.

Participants Adult patients with a new prescription for a PPI individually matched with controls.

Main outcome measures Association of community acquired pneumonia with PPI prescription estimated by three methods: a multivariable Cox model comparing risk in PPI exposed patients with controls, corrected for potential confounders; a self controlled case series; and a prior event rate ratio (PERR) analysis over the 12 month periods before and after the first PPI prescription.

Results 160 000 new PPI users were examined. The adjusted Cox regression showed a risk of community acquired pneumonia 1.67 (95% confidence interval 1.55 to 1.79) times higher for patients exposed to PPI than for controls. In the self controlled case series, among 48 451 PPI exposed patients with a record of community acquired pneumonia, the incidence rate ratio was 1.19 (95% confidence interval 1.14 to 1.25) in the 30 days after PPI prescription but was higher in the 30 days before a PPI prescription (1.92, 1.84 to 2.00). The Cox regressions for prior event rate ratio similarly showed a greater increase in community acquired pneumonia in the year before than the year after PPI prescription, such that the analysis showed a reduced relative risk of pneumonia associated with PPI use (prior event rate ratio 0.91, 95% confidence interval 0.83 to 0.99).

Conclusion The association between the use of PPIs and risk of community acquired pneumonia is likely to be due entirely to confounding factors.

Reference: BMJ 2016;355:i5813

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes


Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.


We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.


At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.


In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 number, NCT01720446.)

N Engl J Med 2016; 375:1834-1844November 10, 2016