Meditation for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: Interventions incorporating meditation to address stress, anxiety, and depression, and improve self-management, are becoming popular for many health conditions. Stress is a risk factor for cardiovascular disease (CVD) and clusters with other modifiable behavioural risk factors, such as smoking. Meditation may therefore be a useful CVD prevention strategy. OBJECTIVES: To determine the effectiveness of meditation, primarily mindfulness-based interventions (MBIs) and transcendental meditation (TM), for the primary and secondary prevention of CVD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trials registers on 14 November 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of 12 weeks or more in adults at high risk of CVD and those with established CVD. We explored four comparisons: MBIs versus active comparators (alternative interventions); MBIs versus non-active comparators (no intervention, wait list, usual care); TM versus active comparators; TM versus non-active comparators. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were CVD clinical events (e.g. cardiovascular mortality), blood pressure, measures of psychological distress and well-being, and adverse events. Secondary outcomes included other CVD risk factors (e.g. blood lipid levels), quality of life, and coping abilities. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 81 RCTs (6971 participants), with most studies at unclear risk of bias. MBIs versus active comparators (29 RCTs, 2883 participants) Systolic (SBP) and diastolic (DBP) blood pressure were reported in six trials (388 participants) where heterogeneity was considerable (SBP: MD -6.08 mmHg, 95% CI -12.79 to 0.63, I2 = 88%; DBP: MD -5.18 mmHg, 95% CI -10.65 to 0.29, I2 = 91%; both outcomes based on low-certainty evidence). There was little or no effect of MBIs on anxiety (SMD -0.06 units, 95% CI -0.25 to 0.13; I2 = 0%; 9 trials, 438 participants; moderate-certainty evidence), or depression (SMD 0.08 units, 95% CI -0.08 to 0.24; I2 = 0%; 11 trials, 595 participants; moderate-certainty evidence). Perceived stress was reduced with MBIs (SMD -0.24 units, 95% CI -0.45 to -0.03; I2 = 0%; P = 0.03; 6 trials, 357 participants; moderate-certainty evidence). There was little to no effect on well-being (SMD -0.18 units, 95% CI -0.67 to 0.32; 1 trial, 63 participants; low-certainty evidence). There was little to no effect on smoking cessation (RR 1.45, 95% CI 0.78 to 2.68; I2 = 79%; 6 trials, 1087 participants; low-certainty evidence). None of the trials reported CVD clinical events or adverse events. MBIs versus non-active comparators (38 RCTs, 2905 participants) Clinical events were reported in one trial (110 participants), providing very low-certainty evidence (RR 0.94, 95% CI 0.37 to 2.42). SBP and DBP were reduced in nine trials (379 participants) but heterogeneity was substantial (SBP: MD -6.62 mmHg, 95% CI -13.15 to -0.1, I2 = 87%; DBP: MD -3.35 mmHg, 95% CI -5.86 to -0.85, I2 = 61%; both outcomes based on low-certainty evidence). There was low-certainty evidence of reductions in anxiety (SMD -0.78 units, 95% CI -1.09 to -0.41; I2 = 61%; 9 trials, 533 participants; low-certainty evidence), depression (SMD -0.66 units, 95% CI -0.91 to -0.41; I2 = 67%; 15 trials, 912 participants; low-certainty evidence) and perceived stress (SMD -0.59 units, 95% CI -0.89 to -0.29; I2 = 70%; 11 trials, 708 participants; low-certainty evidence) but heterogeneity was substantial. Well-being increased (SMD 0.5 units, 95% CI 0.09 to 0.91; I2 = 47%; 2 trials, 198 participants; moderate-certainty evidence). There was little to no effect on smoking cessation (RR 1.36, 95% CI 0.86 to 2.13; I2 = 0%; 2 trials, 453 participants; low-certainty evidence). One small study (18 participants) reported two adverse events in the MBI group, which were not regarded as serious by the study investigators (RR 5.0, 95% CI 0.27 to 91.52; low-certainty evidence). No subgroup effects were seen for SBP, DBP, anxiety, depression, or perceived stress by primary and secondary prevention. TM versus active comparators (8 RCTs, 830 participants) Clinical events were reported in one trial (201 participants) based on low-certainty evidence (RR 0.91, 95% CI 0.56 to 1.49). SBP was reduced (MD -2.33 mmHg, 95% CI -3.99 to -0.68; I2 = 2%; 8 trials, 774 participants; moderate-certainty evidence), with an uncertain effect on DBP (MD -1.15 mmHg, 95% CI -2.85 to 0.55; I2 = 53%; low-certainty evidence). There was little or no effect on anxiety (SMD 0.06 units, 95% CI -0.22 to 0.33; I2 = 0%; 3 trials, 200 participants; low-certainty evidence), depression (SMD -0.12 units, 95% CI -0.31 to 0.07; I2 = 0%; 5 trials, 421 participants; moderate-certainty evidence), or perceived stress (SMD 0.04 units, 95% CI -0.49 to 0.57; I2 = 70%; 3 trials, 194 participants; very low-certainty evidence). None of the trials reported adverse events or smoking rates. No subgroup effects were seen for SBP or DBP by primary and secondary prevention. TM versus non-active comparators (2 RCTs, 186 participants) Two trials (139 participants) reported blood pressure, where reductions were seen in SBP (MD -6.34 mmHg, 95% CI -9.86 to -2.81; I2 = 0%; low-certainty evidence) and DBP (MD -5.13 mmHg, 95% CI -9.07 to -1.19; I2 = 18%; very low-certainty evidence). One trial (112 participants) reported anxiety and depression and found reductions in both (anxiety SMD -0.71 units, 95% CI -1.09 to -0.32; depression SMD -0.48 units, 95% CI -0.86 to -0.11; low-certainty evidence). None of the trials reported CVD clinical events, adverse events, or smoking rates. AUTHORS' CONCLUSIONS: Despite the large number of studies included in the review, heterogeneity was substantial for many of the outcomes, which reduced the certainty of our findings. We attempted to address this by presenting four main comparisons of MBIs or TM versus active or inactive comparators, and by subgroup analyses according to primary or secondary prevention, where there were sufficient studies. The majority of studies were small and there was unclear risk of bias for most domains. Overall, we found very little information on the effects of meditation on CVD clinical endpoints, and limited information on blood pressure and psychological outcomes, for people at risk of or with established CVD. This is a very active area of research as shown by the large number of ongoing studies, with some having been completed at the time of writing this review. The status of all ongoing studies will be formally assessed and incorporated in further updates.

Persistent symptoms are associated with long term effects of COVID-19 among children and young people: Results from a systematic review and meta-analysis of controlled studies.

BACKGROUND: Research on the long-term impact on COVID-19 in children and young people (CYP) has been published at pace. We aimed to update and refine an earlier systematic review and meta-analysis to assess the current evidence for Post-COVID-19 Condition in CYP. METHODS: Studies from the previous systematic review were combined with studies from a systematic search from July 2021 to November 2022 (registration PROSPERO CRD42021233153). Eligible studies included CYP aged ≤19 years with confirmed or probable SARS-CoV-2 infection and symptoms persisting at least 12 weeks. FINDINGS: 55 studies (n = 1,139,299 participants) were included. Over two-hundred symptoms were associated with Post COVID-19 Condition. Gastrointestinal problems, headaches, cough and fever were among the most prevalent symptoms with rates of 50.2%, 35.6%, 34.7% and 25.8% respectively. Twenty-one symptoms from 11 studies were suitable for meta-analysis. There were significantly higher pooled estimates of proportions of symptoms for altered / loss of smell or taste, dyspnoea, fatigue, and myalgia in CYP with confirmed SARS-CoV-2 infection. Heterogeneity was high suggesting substantial variation amongst the included studies. CONCLUSIONS: Many CYP continue to experience symptoms after SARS-CoV-2 infection. Efforts to aid early identification and intervention of those most in need is warranted and the consequences of COVID-19 for CYP call for long-term follow-up.

Low intensity psychological interventions for the treatment of feeding and eating disorders: a systematic review and meta-analysis.

BACKGROUND: Feeding and eating disorders are associated with significant illness burden and costs, yet access to evidence-based care is limited. Low intensity psychological interventions have the potential to increase such access. METHODS: A systematic review and meta-analysis were conducted on the use of low intensity psychological interventions for the treatment of feeding and eating disorders. Studies comparing low intensity psychological interventions against high intensity therapies and non-eating disorder specific psychological interventions were included, as well as those with waiting list control arms. There were three primary outcomes: eating disorder psychopathology, diagnostic and statistical manual of mental disorders (DSM) severity specifier-related outcomes and rates of remission/recovery. RESULTS: Thirty-three studies met the inclusion criteria, comprising 3665 participants, and 30 studies were included in the meta-analysis. Compared to high intensity therapies, low intensity psychological interventions were equivalent on reducing eating disorder psychopathology (g = - 0.13), more effective at improving DSM severity specifier-related outcomes (g = - 0.15), but less likely to achieve remission/recovery (risk ratio (RR) = 0.70). Low intensity psychological interventions were superior to non-eating disorder specific psychological interventions and waiting list controls across all three primary outcomes. CONCLUSION: Overall, findings suggest that low intensity psychological interventions can successfully treat eating disorder symptoms. Few potential moderators had a statistically significant effect on outcome. The number of studies for many comparisons was low and the methodological quality of the studies was poor, therefore results should be interpreted with caution. More research is needed to establish the effectiveness of low intensity psychological interventions for children and young people, as well as for individuals with anorexia nervosa, avoidant/restrictive food intake disorder, pica and rumination disorder.

Feeding and eating disorders can significantly impair health and psychosocial functioning. However, demand for eating disorder services is greater than services' ability to deliver effective treatment. Low intensity psychological interventions, which are brief in nature and require less therapist input than standard treatments, have the potential to bridge this demand-capacity gap. The current review examined the effectiveness of low intensity psychological interventions for the treatment of feeding and eating disorders. Overall, findings suggest that low intensity psychological interventions can successfully treat eating disorder symptoms, particularly binge eating-related symptoms. Given their relatively low costs and ease of accessibility, such interventions can help people to access treatment at a time when this is so desperately needed. More research is needed to determine the value of low intensity psychological interventions for children and adolescents, and people with feeding and eating disorders that are not characterised by recurrent binge eating, such as anorexia nervosa, ARFID, pica and rumination disorder.

Vegan dietary pattern for the primary and secondary prevention of cardiovascular diseases.

BACKGROUND: Diet plays a major role in the aetiology of cardiovascular disease (CVD) and as a modifiable risk factor is the focus of many prevention strategies. Recently vegan diets have gained popularity and there is a need to synthesise existing clinical trial evidence for their potential in CVD prevention. OBJECTIVES: To determine the effectiveness of following a vegan dietary pattern for the primary and secondary prevention of CVD. SEARCH METHODS: We searched the following electronic databases on 4 February 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Web of Science Core Collection. We also searched ClinicalTrials.gov in January 2021. We applied no language restrictions. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) in healthy adults and adults at high risk of CVD (primary prevention) and those with established CVD (secondary prevention). A vegan dietary pattern excludes meat, fish, eggs, dairy and honey; the intervention could be dietary advice, provision of relevant foods, or both. The comparison group received either no intervention, minimal intervention, or another dietary intervention. Outcomes included clinical events and CVD risk factors. We included only studies with follow-up periods of 12 weeks or more, defined as the intervention period plus post-intervention follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data and assessed risks of bias. We used GRADE to assess the certainty of the evidence. We conducted three main comparisons: 1. Vegan dietary intervention versus no intervention or minimal intervention for primary prevention; 2. Vegan dietary intervention versus another dietary intervention for primary prevention; 3. Vegan dietary intervention versus another dietary intervention for secondary prevention. MAIN RESULTS: Thirteen RCTs (38 papers, 7 trial registrations) and eight ongoing trials met our inclusion criteria. Most trials contributed to primary prevention: comparisons 1 (four trials, 466 participants randomised) and comparison 2 (eight trials, 409 participants randomised). We included only one secondary prevention trial for comparison 3 (63 participants randomised). None of the trials reported on clinical endpoints. Other primary outcomes included lipid levels and blood pressure. For comparison 1 there was moderate-certainty evidence from four trials with 449 participants that a vegan diet probably led to a small reduction in total cholesterol (mean difference (MD) -0.24 mmol/L, 95% confidence interval (CI) -0.36 to -0.12) and low-density lipoprotein (LDL) cholesterol (MD -0.22 mmol/L, 95% CI -0.32 to -0.11), a very small decrease in high-density lipoprotein (HDL) levels (MD -0.08 mmol/L, 95% CI -0.11 to -0.04) and a very small increase in triglyceride levels (MD 0.11 mmol/L, 95% CI 0.01 to 0.21). The very small changes in HDL and triglyceride levels are in the opposite direction to that expected. There was a lack of evidence for an effect with the vegan dietary intervention on systolic blood pressure (MD 0.94 mmHg, 95% CI -1.18 to 3.06; 3 trials, 374 participants) and diastolic blood pressure (MD -0.27 mmHg, 95% CI -1.67 to 1.12; 3 trials, 372 participants) (low-certainty evidence). For comparison 2 there was a lack of evidence for an effect of the vegan dietary intervention on total cholesterol levels (MD -0.04 mmol/L, 95% CI -0.28 to 0.20; 4 trials, 163 participants; low-certainty evidence). There was probably little or no effect of the vegan dietary intervention on LDL (MD -0.05 mmol/L, 95% CI -0.21 to 0.11; 4 trials, 244 participants) or HDL cholesterol levels (MD -0.01 mmol/L, 95% CI -0.08 to 0.05; 5 trials, 256 participants) or triglycerides (MD 0.21 mmol/L, 95% CI -0.07 to 0.49; 5 trials, 256 participants) compared to other dietary interventions (moderate-certainty evidence). We are very uncertain about any effect of the vegan dietary intervention on systolic blood pressure (MD 0.02 mmHg, 95% CI -3.59 to 3.62)  or diastolic blood pressure (MD 0.63 mmHg, 95% CI -1.54 to 2.80; 5 trials, 247 participants (very low-certainty evidence)). Only one trial (63 participants) contributed to comparison 3, where there was a lack of evidence for an effect of the vegan dietary intervention on lipid levels or blood pressure compared to other dietary interventions (low- or very low-certainty evidence). Four trials reported on adverse events, which were absent or minor. AUTHORS' CONCLUSIONS: Studies were generally small with few participants contributing to each comparison group. None of the included studies report on CVD clinical events. There is currently insufficient information to draw conclusions about the effects of vegan dietary interventions on CVD risk factors. The eight ongoing studies identified will add to the evidence base, with all eight reporting on primary prevention. There is a paucity of evidence for secondary prevention.

Mediterranean-Style Diet for the Primary and Secondary Prevention of Cardiovascular Disease: A Cochrane Review.

Background: Diet plays a major role in cardiovascular disease (CVD) risk. Objectives: To determine the effectiveness of a Mediterranean-style diet for the primary and secondary prevention of CVD. Methods: We searched for randomised controlled trials (RCTs) of Mediterranean-style diets in healthy adults and those at increased risk of CVD (primary prevention) and with established CVD (secondary prevention). Results: Thirty RCTs were included, 22 in primary prevention and eight in secondary prevention. Clinical endpoints were reported in two trials where there was moderate quality evidence for a reduction in strokes for primary prevention, and low quality evidence for a reduction in total and CVD mortality in secondary prevention. We found moderate quality evidence of improvement in CVD risk factors for primary prevention and low quality evidence of little or no effect in secondary prevention. Conclusions: There is still some uncertainty regarding the effects of a Mediterranean-style diet in CVD prevention.

Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.

BACKGROUND: Atrial fibrillation is the most frequent sustained arrhythmia. Atrial fibrillation often recurs after restoration of normal sinus rhythm. Antiarrhythmic drugs have been widely used to prevent recurrence. This is an update of a review previously published in 2006, 2012 and 2015. OBJECTIVES: To determine the effects of long-term treatment with antiarrhythmic drugs on death, stroke, drug adverse effects and recurrence of atrial fibrillation in people who had recovered sinus rhythm after having atrial fibrillation. SEARCH METHODS: We updated the searches of CENTRAL, MEDLINE and Embase in January 2019, and ClinicalTrials.gov and WHO ICTRP in February 2019. We checked the reference lists of retrieved articles, recent reviews and meta-analyses. SELECTION CRITERIA: Two authors independently selected randomised controlled trials (RCTs) comparing any antiarrhythmic drug with a control (no treatment, placebo, drugs for rate control) or with another antiarrhythmic drug in adults who had atrial fibrillation and in whom sinus rhythm was restored, spontaneously or by any intervention. We excluded postoperative atrial fibrillation. DATA COLLECTION AND ANALYSIS: Two authors independently assessed quality and extracted data. We pooled studies, if appropriate, using Mantel-Haenszel risk ratios (RR), with 95% confidence intervals (CI). All results were calculated at one year of follow-up or the nearest time point. MAIN RESULTS: This update included one new study (100 participants) and excluded one previously included study because of double publication. Finally, we included 59 RCTs comprising 20,981 participants studying quinidine, disopyramide, propafenone, flecainide, metoprolol, amiodarone, dofetilide, dronedarone and sotalol. Overall, mean follow-up was 10.2 months.All-cause mortalityHigh-certainty evidence from five RCTs indicated that treatment with sotalol was associated with a higher all-cause mortality rate compared with placebo or no treatment (RR 2.23, 95% CI 1.03 to 4.81; participants = 1882). The number need to treat for an additional harmful outcome (NNTH) for sotalol was 102 participants treated for one year to have one additional death. Low-certainty evidence from six RCTs suggested that risk of mortality may be higher in people taking quinidine (RR 2.01, 95% CI 0.84 to 4.77; participants = 1646). Moderate-certainty evidence showed increased RR for mortality but with very wide CIs for metoprolol (RR 2.02, 95% CI 0.37 to 11.05, 2 RCTs, participants = 562) and amiodarone (RR 1.66, 95% CI 0.55 to 4.99, 2 RCTs, participants = 444), compared with placebo.We found little or no difference in mortality with dofetilide (RR 0.98, 95% CI 0.76 to 1.27; moderate-certainty evidence) or dronedarone (RR 0.86, 95% CI 0.68 to 1.09; high-certainty evidence) compared to placebo/no treatment. There were few data on mortality for disopyramide, flecainide and propafenone, making impossible a reliable estimation for those drugs.Withdrawals due to adverse eventsAll analysed drugs increased withdrawals due to adverse effects compared to placebo or no treatment (quinidine: RR 1.56, 95% CI 0.87 to 2.78; disopyramide: RR 3.68, 95% CI 0.95 to 14.24; propafenone: RR 1.62, 95% CI 1.07 to 2.46; flecainide: RR 15.41, 95% CI 0.91 to 260.19; metoprolol: RR 3.47, 95% CI 1.48 to 8.15; amiodarone: RR 6.70, 95% CI 1.91 to 23.45; dofetilide: RR 1.77, 95% CI 0.75 to 4.18; dronedarone: RR 1.58, 95% CI 1.34 to 1.85; sotalol: RR 1.95, 95% CI 1.23 to 3.11). Certainty of the evidence for this outcome was low for disopyramide, amiodarone, dofetilide and flecainide; moderate to high for the remaining drugs.ProarrhythmiaVirtually all studied antiarrhythmics showed increased proarrhythmic effects (counting both tachyarrhythmias and bradyarrhythmias attributable to treatment) (quinidine: RR 2.05, 95% CI 0.95 to 4.41; disopyramide: no data; flecainide: RR 4.80, 95% CI 1.30 to 17.77; metoprolol: RR 18.14, 95% CI 2.42 to 135.66; amiodarone: RR 2.22, 95% CI 0.71 to 6.96; dofetilide: RR 5.50, 95% CI 1.33 to 22.76; dronedarone: RR 1.95, 95% CI 0.77 to 4.98; sotalol: RR 3.55, 95% CI 2.16 to 5.83); with the exception of propafenone (RR 1.32, 95% CI 0.39 to 4.47) for which the certainty of evidence was very low and we were uncertain about the effect. Certainty of the evidence for this outcome for the other drugs was moderate to high.StrokeEleven studies reported stroke outcomes with quinidine, disopyramide, flecainide, amiodarone, dronedarone and sotalol. High-certainty evidence from two RCTs suggested that dronedarone may be associated with reduced risk of stroke (RR 0.66, 95% CI 0.47 to 0.95; participants = 5872). This result is attributed to one study dominating the meta-analysis and has yet to be reproduced in other studies. There was no apparent effect on stroke rates with the other antiarrhythmics.Recurrence of atrial fibrillationModerate- to high-certainty evidence, with the exception of disopyramide which was low-certainty evidence, showed that all analysed drugs, including metoprolol, reduced recurrence of atrial fibrillation (quinidine: RR 0.83, 95% CI 0.78 to 0.88; disopyramide: RR 0.77, 95% CI 0.59 to 1.01; propafenone: RR 0.67, 95% CI 0.61 to 0.74; flecainide: RR 0.65, 95% CI 0.55 to 0.77; metoprolol: RR 0.83 95% CI 0.68 to 1.02; amiodarone: RR 0.52, 95% CI 0.46 to 0.58; dofetilide: RR 0.72, 95% CI 0.61 to 0.85; dronedarone: RR 0.85, 95% CI 0.80 to 0.91; sotalol: RR 0.83, 95% CI 0.80 to 0.87). Despite this reduction, atrial fibrillation still recurred in 43% to 67% of people treated with antiarrhythmics. AUTHORS' CONCLUSIONS: There is high-certainty evidence of increased mortality associated with sotalol treatment, and low-certainty evidence suggesting increased mortality with quinidine, when used for maintaining sinus rhythm in people with atrial fibrillation. We found few data on mortality in people taking disopyramide, flecainide and propafenone, so it was not possible to make a reliable estimation of the mortality risk for these drugs. However, we did find moderate-certainty evidence of marked increases in proarrhythmia and adverse effects with flecainide.Overall, there is evidence showing that antiarrhythmic drugs increase adverse events, increase proarrhythmic events and some antiarrhythmics may increase mortality. Conversely, although they reduce recurrences of atrial fibrillation, there is no evidence of any benefit on other clinical outcomes, compared with placebo or no treatment.

Mediterranean-style diet for the primary and secondary prevention of cardiovascular disease.

BACKGROUND: The Seven Countries study in the 1960s showed that populations in the Mediterranean region experienced lower coronary heart disease (CHD) mortality probably as a result of different dietary patterns. Later observational studies have confirmed the benefits of adherence to a Mediterranean dietary pattern on cardiovascular disease (CVD) risk factors but clinical trial evidence is more limited. OBJECTIVES: To determine the effectiveness of a Mediterranean-style diet for the primary and secondary prevention of CVD. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9); MEDLINE (Ovid, 1946 to 25 September 2018); Embase (Ovid, 1980 to 2018 week 39); Web of Science Core Collection (Thomson Reuters, 1900 to 26 September 2018); DARE Issue 2 of 4, 2015 (Cochrane Library); HTA Issue 4 of 4, 2016 (Cochrane Library); NHS EED Issue 2 of 4, 2015 (Cochrane Library). We searched trial registers and applied no language restrictions. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) in healthy adults and adults at high risk of CVD (primary prevention) and those with established CVD (secondary prevention). Both of the following key components were required to reach our definition of a Mediterranean-style diet: high monounsaturated/saturated fat ratio (use of olive oil as main cooking ingredient and/or consumption of other traditional foods high in monounsaturated fats such as tree nuts) and a high intake of plant-based foods, including fruits, vegetables and legumes. Additional components included: low to moderate red wine consumption; high consumption of whole grains and cereals; low consumption of meat and meat products and increased consumption of fish; moderate consumption of milk and dairy products. The intervention could be dietary advice, provision of relevant foods, or both. The comparison group received either no intervention, minimal intervention, usual care or another dietary intervention. Outcomes included clinical events and CVD risk factors. We included only studies with follow-up periods of three months or more defined as the intervention period plus post intervention follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data and assessed risk of bias. We conducted four main comparisons:1. Mediterranean dietary intervention versus no intervention or minimal intervention for primary prevention;2. Mediterranean dietary intervention versus another dietary intervention for primary prevention;3. Mediterranean dietary intervention versus usual care for secondary prevention;4. Mediterranean dietary intervention versus another dietary intervention for secondary prevention. MAIN RESULTS: In this substantive review update, 30 RCTs (49 papers) (12,461 participants randomised) and seven ongoing trials met our inclusion criteria. The majority of trials contributed to primary prevention: comparisons 1 (nine trials) and 2 (13 trials). Secondary prevention trials were included for comparison 3 (two trials) and comparison 4 (four trials plus an additional two trials that were excluded from the main analyses due to published concerns regarding the reliability of the data).Two trials reported on adverse events where these were absent or minor (low- to moderate-quality evidence). No trials reported on costs or health-related quality of life.Primary preventionThe included studies for comparison 1 did not report on clinical endpoints (CVD mortality, total mortality or non-fatal endpoints such as myocardial infarction or stroke). The PREDIMED trial (included in comparison 2) was retracted and re-analysed following concerns regarding randomisation at two of 11 sites. Low-quality evidence shows little or no effect of the PREDIMED (7747 randomised) intervention (advice to follow a Mediterranean diet plus supplemental extra-virgin olive oil or tree nuts) compared to a low-fat diet on CVD mortality (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.50 to 1.32) or total mortality (HR 1.0, 95% CI 0.81 to 1.24) over 4.8 years. There was, however, a reduction in the number of strokes with the PREDIMED intervention (HR 0.60, 95% CI 0.45 to 0.80), a decrease from 24/1000 to 14/1000 (95% CI 11 to 19), moderate-quality evidence). For CVD risk factors for comparison 1 there was low-quality evidence for a possible small reduction in total cholesterol (-0.16 mmol/L, 95% CI -0.32 to 0.00) and moderate-quality evidence for a reduction in systolic (-2.99 mmHg (95% CI -3.45 to -2.53) and diastolic blood pressure (-2.0 mmHg, 95% CI -2.29 to -1.71), with low or very low-quality evidence of little or no effect on LDL or HDL cholesterol or triglycerides. For comparison 2 there was moderate-quality evidence of a possible small reduction in LDL cholesterol (-0.15 mmol/L, 95% CI -0.27 to -0.02) and triglycerides (-0.09 mmol/L, 95% CI -0.16 to -0.01) with moderate or low-quality evidence of little or no effect on total or HDL cholesterol or blood pressure.Secondary preventionFor secondary prevention, the Lyon Diet Heart Study (comparison 3) examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared to usual care in 605 CHD patients over 46 months and there was low-quality evidence of a reduction in adjusted estimates for CVD mortality (HR 0.35, 95% CI 0.15 to 0.82) and total mortality (HR 0.44, 95% CI 0.21 to 0.92) with the intervention. Only one small trial (101 participants) provided unadjusted estimates for composite clinical endpoints for comparison 4 (very low-quality evidence of uncertain effect). For comparison 3 there was low-quality evidence of little or no effect of a Mediterranean-style diet on lipid levels and very low-quality evidence for blood pressure. Similarly, for comparison 4 where only two trials contributed to the analyses there was low or very low-quality evidence of little or no effect of the intervention on lipid levels or blood pressure. AUTHORS' CONCLUSIONS: Despite the relatively large number of studies included in this review, there is still some uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and CVD risk factors for both primary and secondary prevention. The quality of evidence for the modest benefits on CVD risk factors in primary prevention is low or moderate, with a small number of studies reporting minimal harms. There is a paucity of evidence for secondary prevention. The ongoing studies may provide more certainty in the future.

Disease management interventions for heart failure.

BACKGROUND: Despite advances in treatment, the increasing and ageing population makes heart failure an important cause of morbidity and death worldwide. It is associated with high healthcare costs, partly driven by frequent hospital readmissions. Disease management interventions may help to manage people with heart failure in a more proactive, preventative way than drug therapy alone. This is the second update of a review published in 2005 and updated in 2012. OBJECTIVES: To compare the effects of different disease management interventions for heart failure (which are not purely educational in focus), with usual care, in terms of death, hospital readmissions, quality of life and cost-related outcomes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CINAHL for this review update on 9 January 2018 and two clinical trials registries on 4 July 2018. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least six months' follow-up, comparing disease management interventions to usual care for adults who had been admitted to hospital at least once with a diagnosis of heart failure. There were three main types of intervention: case management; clinic-based interventions; multidisciplinary interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Outcomes of interest were mortality due to heart failure, mortality due to any cause, hospital readmission for heart failure, hospital readmission for any cause, adverse effects, quality of life, costs and cost-effectiveness. MAIN RESULTS: We found 22 new RCTs, so now include 47 RCTs (10,869 participants). Twenty-eight were case management interventions, seven were clinic-based models, nine were multidisciplinary interventions, and three could not be categorised as any of these. The included studies were predominantly in an older population, with most studies reporting a mean age of between 67 and 80 years. Seven RCTs were in upper-middle-income countries, the rest were in high-income countries.Only two multidisciplinary-intervention RCTs reported mortality due to heart failure. Pooled analysis gave a risk ratio (RR) of 0.46 (95% confidence interval (CI) 0.23 to 0.95), but the very low-quality evidence means we are uncertain of the effect on mortality due to heart failure. Based on this limited evidence, the number needed to treat for an additional beneficial outcome (NNTB) is 12 (95% CI 9 to 126).Twenty-six case management RCTs reported all-cause mortality, with low-quality evidence indicating that these may reduce all-cause mortality (RR 0.78, 95% CI 0.68 to 0.90; NNTB 25, 95% CI 17 to 54). We pooled all seven clinic-based studies, with low-quality evidence suggesting they may make little to no difference to all-cause mortality. Pooled analysis of eight multidisciplinary studies gave moderate-quality evidence that these probably reduce all-cause mortality (RR 0.67, 95% CI 0.54 to 0.83; NNTB 17, 95% CI 12 to 32).We pooled data on heart failure readmissions from 12 case management studies. Moderate-quality evidence suggests that they probably reduce heart failure readmissions (RR 0.64, 95% CI 0.53 to 0.78; NNTB 8, 95% CI 6 to 13). We were able to pool only two clinic-based studies, and the moderate-quality evidence suggested that there is probably little or no difference in heart failure readmissions between clinic-based interventions and usual care (RR 1.01, 95% CI 0.87 to 1.18). Pooled analysis of five multidisciplinary interventions gave low-quality evidence that these may reduce the risk of heart failure readmissions (RR 0.68, 95% CI 0.50 to 0.92; NNTB 11, 95% CI 7 to 44).Meta-analysis of 14 RCTs gave moderate-quality evidence that case management probably slightly reduces all-cause readmissions (RR 0.92, 95% CI 0.83 to 1.01); a decrease from 491 to 451 in 1000 people (95% CI 407 to 495). Pooling four clinic-based RCTs gave low-quality and somewhat heterogeneous evidence that these may result in little or no difference in all-cause readmissions (RR 0.90, 95% CI 0.72 to 1.12). Low-quality evidence from five RCTs indicated that multidisciplinary interventions may slightly reduce all-cause readmissions (RR 0.85, 95% CI 0.71 to 1.01); a decrease from 450 to 383 in 1000 people (95% CI 320 to 455).Neither case management nor clinic-based intervention RCTs reported adverse effects. Two multidisciplinary interventions reported that no adverse events occurred. GRADE assessment of moderate quality suggested that there may be little or no difference in adverse effects between multidisciplinary interventions and usual care.Quality of life was generally poorly reported, with high attrition. Low-quality evidence means we are uncertain about the effect of case management and multidisciplinary interventions on quality of life. Four clinic-based studies reported quality of life but we could not pool them due to differences in reporting. Low-quality evidence indicates that clinic-based interventions may result in little or no difference in quality of life.Four case management programmes had cost-effectiveness analyses, and seven reported cost data. Low-quality evidence indicates that these may reduce costs and may be cost-effective. Two clinic-based studies reported cost savings. Low-quality evidence indicates that clinic-based interventions may reduce costs slightly. Low-quality data from one multidisciplinary intervention suggested this may be cost-effective from a societal perspective but less so from a health-services perspective. AUTHORS' CONCLUSIONS: We found limited evidence for the effect of disease management programmes on mortality due to heart failure, with few studies reporting this outcome. Case management may reduce all-cause mortality, and multidisciplinary interventions probably also reduce all-cause mortality, but clinic-based interventions had little or no effect on all-cause mortality. Readmissions due to heart failure or any cause were probably reduced by case-management interventions. Clinic-based interventions probably make little or no difference to heart failure readmissions and may result in little or no difference in readmissions for any cause. Multidisciplinary interventions may reduce the risk of readmission for heart failure or for any cause. There was a lack of evidence for adverse effects, and conclusions on quality of life remain uncertain due to poor-quality data. Variations in study location and time of occurrence hamper attempts to review costs and cost-effectiveness.The potential to improve quality of life is an important consideration but remains poorly reported. Improved reporting in future trials would strengthen the evidence for this patient-relevant outcome.

Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events.

BACKGROUND: Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease. This is an update to a previously published review from 2011. OBJECTIVES: To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or were at high risk of atherothrombotic disease, but did not have a coronary stent. SEARCH METHODS: We updated the searches of CENTRAL (2017, Issue 6), MEDLINE (Ovid, 1946 to 4 July 2017) and Embase (Ovid, 1947 to 3 July 2017) on 4 July 2017. We also searched ClinicalTrials.gov and the WHO ICTRP portal, and handsearched reference lists. We applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials comparing over 30 days use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in people with coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease. We excluded studies including only people with coronary drug-eluting stent (DES) or non-DES, or both. DATA COLLECTION AND ANALYSIS: We collected data on mortality from cardiovascular causes, all-cause mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, major and minor bleeding. The overall treatment effect was estimated by the pooled risk ratio (RR) with 95% confidence interval (CI), using a fixed-effect model (Mantel-Haenszel); we used a random-effects model in cases of moderate or severe heterogeneity (I2 ≥ 30%). We assessed the quality of the evidence using the GRADE approach. We used GRADE profiler (GRADE Pro) to import data from Review Manager to create a 'Summary of findings' table. MAIN RESULTS: The search identified 13 studies in addition to the two studies in the previous version of our systematic review. Overall, we included data from 15 trials with 33,970 people. We completed a 'Risk of bias' assessment for all studies. The risk of bias was low in four trials because they were at low risk of bias for all key domains (random sequence generation, allocation concealment, blinding, selective outcome reporting and incomplete outcome data), even if some of them were funded by the pharmaceutical industry.Analysis showed no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI 0.88 to 1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI 0.87 to 1.25; participants = 32,908; studies = 9; low quality evidence).There was a lower risk of fatal and non-fatal myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI 0.69 to 0.90; participants = 16,175; studies = 6; moderate quality evidence). There was a reduction in the risk of fatal and non-fatal ischaemic stroke (RR 0.73, 95% CI 0.59 to 0.91; participants = 4006; studies = 5; moderate quality evidence).However, there was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI 1.25 to 1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI 1.75 to 2.36; participants = 14,731; studies = 8; moderate quality evidence).Overall, we would expect 13 myocardial infarctions and 23 ischaemic strokes be prevented for every 1000 patients treated with the combination in a median follow-up period of 12 months, but 9 major bleeds and 33 minor bleeds would be caused during a median follow-up period of 10.5 and 6 months, respectively. AUTHORS' CONCLUSIONS: The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infarction and ischaemic stroke, and an increased risk of major and minor bleeding compared with aspirin alone. According to GRADE criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low quality evidence) and adverse events (very low quality evidence).

Associations between inflammatory and immune response genes and adverse respiratory outcomes following exposure to outdoor air pollution: a HuGE systematic review.

Variants of inflammatory and immune response genes have been associated with adverse respiratory outcomes following exposure to air pollution. However, the genes involved and their associations are not well characterized, and there has been no systematic review. Thus, we conducted a review following the guidelines of the Human Genome Epidemiology Network. Six observational studies and 2 intervention studies with 14,903 participants were included (2001-2010). Six studies showed at least 1 significant gene-pollutant interaction. Meta-analysis was not possible due to variations in genes, pollutants, exposure estimates, and reported outcomes. The most commonly studied genes were tumor necrosis factor α (TNFA) (n = 6) and toll-like receptor 4 (TLR4) (n = 3). TNFA -308G>A modified the action of ozone and nitrogen dioxide on lung function, asthma risk, and symptoms; however, the direction of association varied between studies. The TLR4 single-nucleotide polymorphisms rs1927911, rs10759931, and rs6478317 modified the association of particulate matter and nitrogen dioxide with asthma. The transforming growth factor ß1 (TGFB1) polymorphism -509C>T also modified the association of pollutants with asthma. This review indicates that genes controlling innate immune recognition of foreign material (TLR4) and the subsequent inflammatory response (TGFB1, TLR4) modify the associations of exposure to air pollution with respiratory function. The associations observed have biological plausibility; however, larger studies with improved reporting are needed to confirm these findings.

Vitamin A and carotenoids and the risk of Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Vitamin A and carotenoids are involved in signalling pathways regulating gene expression in many organs, including the brain. The dopaminergic system is a target of retinoic acid action in the central nervous system. The aim of this review is to assess the epidemiological evidence on the association between blood levels or dietary intakes of vitamin A and carotenoids and risk of Parkinson's disease (PD). METHODS: PubMed and ISI Web of Science were searched for relevant papers from 1990 to April 2013. Data reported in epidemiological studies assessing the association between vitamin A and/or carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, lutein, lycopene, zeaxanthin and canthaxanthin) and PD were extracted for a narrative synthesis and meta-analysis. RESULTS: Thirteen papers were included out of a total of 362 potentially relevant; of these, eight contributed to the meta-analysis. No statistically significant pooled estimate between micronutrient and PD was detected. Forest plots suggest possible non-significant inverse pooled estimates of α-carotene and ß-carotene and risk of PD. A significant association between lutein intake and PD risk was detected in case-control studies only. CONCLUSIONS: Data published to date are insufficient for drawing definite conclusions about the epidemiological evidence on the association between blood levels or dietary intakes of vitamin A and carotenoids and the risk of PD. Results should be interpreted particularly cautiously given the limitation of the present meta-analysis and the potential publication bias. Authors are urged to follow more closely the recommendations for reporting epidemiological studies in order to enhance the capacity for synthesising the evidence.

Clinical service organisation for heart failure.

BACKGROUND: Chronic heart failure (CHF) is a serious, common condition associated with frequent hospitalisation. Several different disease management interventions (clinical service organisation interventions) for patients with CHF have been proposed. OBJECTIVES: To update the previously published review which assessed the effectiveness of disease management interventions for patients with CHF. SEARCH METHODS: A number of databases were searched for the updated review: CENTRAL, (the Cochrane Central Register of Controlled Trials) and DARE, on The Cochrane Library, ( Issue 1 2009); MEDLINE (1950-January 2009); EMBASE (1980-January 2009); CINAHL (1982-January 2009); AMED (1985-January 2009). For the original review (but not the update) we had also searched: Science Citation Index Expanded (1981-2001); SIGLE (1980-2003); National Research Register (2003) and NHS Economic Evaluations Database (2001). We also searched reference lists of included studies for both the original and updated reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs) with at least six months follow up, comparing disease management interventions specifically directed at patients with CHF to usual care. DATA COLLECTION AND ANALYSIS: At least two reviewers independently extracted data and assessed study quality. Study authors were contacted for further information where necessary. Data were analysed and presented as odds ratios (OR) with 95% confidence intervals (CI). MAIN RESULTS: Twenty five trials (5,942 people) were included. Interventions were classified by: (1) case management interventions (intense monitoring of patients following discharge often involving telephone follow up and home visits); (2) clinic interventions (follow up in a CHF clinic) and (3) multidisciplinary interventions (holistic approach bridging the gap between hospital admission and discharge home delivered by a team). The components, intensity and duration of the interventions varied, as did the 'usual care' comparator provided in different trials.Case management interventions were associated with reduction in all cause mortality at 12 months follow up, OR 0.66 (95% CI 0.47 to 0.91, but not at six months. No reductions were seen for deaths from CHF or cardiovascular causes. However, case management type interventions reduced CHF related readmissions at six month (OR 0.64, 95% CI 0.46 to 0.88, P = 0.007) and 12 month follow up (OR 0.47, 95% CI 0.30 to 0.76). Impact of these interventions on all cause hospital admissions was not apparent at six months but was at 12 months (OR 0.75, 95% CI 0.57 to 0.99, I(2) = 58%).   CHF clinic interventions (for six and 12 month follow up) revealed non-significant reductions in all cause mortality, CHF related admissions and all cause readmissions. Mortality was not reduced in the two studies that looked at multidisciplinary interventions. However, both all cause and CHF related readmissions were reduced (OR 0.46, 95% CI 0.46-0.69, and 0.45, 95% CI 0.28-0.72, respectively).  AUTHORS' CONCLUSIONS: Amongst CHF patients who have previously been admitted to hospital for this condition there is now good evidence that case management type interventions led by a heart failure specialist nurse reduces CHF related readmissions after 12 months follow up, all cause readmissions and all cause mortality.  It is not possible to say what the optimal components of these case management type interventions are, however telephone follow up by the nurse specialist was a common component.Multidisciplinary interventions may be effective in reducing both CHF and all cause readmissions. There is currently limited evidence to support interventions whose major component is follow up in a CHF clinic.

Treatment for tobacco dependence: a potential application for stratified medicine?

Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on society. Therefore, ways of helping people to overcome nicotine dependence are a key element of strategies aimed at improving public health. Current treatments are only partially effective and there is a need to develop more efficient approaches to help smokers to stop. There exists a substantial genetic variability in smoking behavior and the likelihood of cessation - tailoring treatment according to an individual's genetic profile is now technologically feasible and could lead to more successful cessation attempts. Here we review studies of the genetic effects on smoking cessation in randomized controlled trials of pharmacological therapy and discuss the potential value of a personalized approach to help people stop smoking.

Time to full publication of studies of anticancer drugs for breast cancer, and the potential for publication bias.

OBJECTIVES: Nonpublication of results of clinical trials can contribute to inappropriate medical decisions. The primary aim of this systematic review was to investigate publication delays between conference abstracts and full journal publications from randomized controlled trial results of new anticancer agents for breast cancer. The review was restricted to anticancer agents previously, or due to be, appraised in the United Kingdom by the National Institute for Health and Clinical Excellence. A secondary objective was to identify whether there are any apparent biases in the publication and reporting of these trials. METHODS: We searched six electronic databases up to August 2007, including Medline and the Cochrane Library. Two reviewers independently selected studies, extracted and assessed the data. RESULTS: Six anticancer treatments were identified: docetaxel, paclitaxel, trastuzumab, gemcitabine, lapatinib, and bevacizumab. Of eighteen included trials, only four publications from three trials reported the same outcomes in both abstract and full publication. Time delays ranged from 5 to 19 months. Eleven trial abstracts were still without a full publication at the end of our searches, varying from 3 to 38 months since abstract publication. Observational analysis revealed no particular publishing biases. CONCLUSIONS: Whereas delays in publication appear reasonable over a period of months, many were not published in full over a period of years and others would appear to be unlikely to ever be published. Further research should investigate the impact of publication delays on the availability of new drug treatments in clinical practice.

Evaluation of the cost-effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom.

OBJECTIVES: The aim of this study was to assess the cost-effectiveness of drotrecogin alfa (activated) compared with best supportive care in a UK cohort of adult intensive-care patients with severe sepsis. METHODS: A systematic review of evidence on the clinical- and cost-effectiveness of drotrecogin alfa (activated) was undertaken, and a decision-analytic model was developed to estimate the cost-effectiveness of treatment in the United Kingdom. Trial data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study have been synthesized with other data, including UK data on severe sepsis, to estimate the costs and consequences of treatment over time. RESULTS: For patients with severe sepsis and multiple organ dysfunction, the estimates of cost per life year and cost per quality-adjusted life year (QALY) are pounds 4931 and pounds 8228, respectively. For patients with severe sepsis alone, the cost per life-year and cost per QALY are pouhds 5495 and pounds 9161, respectively. CONCLUSIONS: Whereas the therapeutic cost for drotrecogin alfa (activated) appears high (at around pounds 5000 per patient) and the potential impact on the provider budget is considerable, drotrecogin alfa (activated) is clinically effective, represents a cost-effective use of resources, and is a significant advance in the treatment of severe sepsis in patients requiring intensive care.

A systematic review of the clinical and cost-effectiveness of memantine in patients with moderately severe to severe Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and is characterised by a worsening of cognition, functional ability, and behaviour and mood. The objective of this study was to review the clinical and cost-effectiveness of memantine for the treatment of patients with moderately severe to severe AD. To achieve this, a systematic search and review of the clinical and cost effectiveness literature for memantine was undertaken. The literature search covered the period from the inception of MEDLINE, Cochrane Library, EMBASE and other electronic databases until July 2004. The search included randomised controlled trials (RCTs) and full economic evaluations that assessed the use of memantine in patients with moderately severe to severe AD. Two published RCTs were included in this review; in one of these trials the participants were already being treated with donepezil. The two RCTs showed benefit for patients receiving memantine compared with placebo on the outcome measures of the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia, the Clinician's Interview-Based Impression of Change Plus Caregiver Input, and the Severe Impairment Battery, and that memantine appeared to be slightly more effective in patients already receiving a stable dose of donepezil. Five cost-effectiveness studies were included in the review. Although these studies reported cost reductions and improved outcomes with memantine, the evaluations were based on a number of assumptions. In conclusion, memantine appears to be beneficial when assessed using functional and global measurements. However, the effect of memantine on cognitive scores and behaviour and mood outcomes is less clear. Cost-effectiveness is dependent upon assumptions surrounding clinical effect and context-specific cost data.

Modelling the cost effectiveness of cholinesterase inhibitors in the management of mild to moderately severe Alzheimer's disease.

OBJECTIVE: To estimate the cost effectiveness (from the UK NHS and personal social services perspective) of the cholinesterase inhibitors donepezil, rivastigmine and galantamine compared with usual care in the treatment of mild to moderately severe Alzheimer's disease. Patients had a mean age of 74 years, a mean disease duration of 1 year and a mean Alzheimer's disease assessment scale-cognitive subscale score of 24. METHODS: A pharmacoeconomic model was used to predict long-term outcomes over a 5-year time horizon and to estimate the cost effectiveness of cholinesterase inhibitors for the management of Alzheimer's disease. The model structure is informed by a systematic review of the literature on the clinical and cost effectiveness of cholinesterase inhibitors and a review of the literature on the costs and outcomes associated with treatment for Alzheimer's disease. The main outcome measure used was the cost per quality-adjusted life-year (QALY) gained. All healthcare costs (excluding cholinesterase inhibitor costs) were indexed to pounds sterling (2003 values). Drug costs are 2005 values. Multivariate probabilistic sensitivity analysis and scenario analysis were undertaken to assess uncertainty in the results. RESULTS: The clinical benefits on cognition from treatment with cholinesterase inhibitors resulted in an incremental cost per QALY gained ranging from 53,780 pounds sterling to 74,735 pounds sterling, over 5 years (vs usual care). Uncertainty analysis suggests that the probability of any of these treatments having an incremental cost per QALY of < 30,000 pounds sterling is < 21%. The key determinants of cost effectiveness were the effectiveness of treatment, the mean treatment cost and the cost savings associated with an expected delay in disease progression. CONCLUSIONS: Results presented in this paper suggest that the use of cholinesterase inhibitors may not be a cost-effective use of NHS resources. Guidance from the National Institute for Health and Clinical Effectiveness (NICE) in the UK on their judgements surrounding the acceptability of technologies as an effective use of resources, indicates there would need to be special reasons for accepting cholinesterase inhibitors as a cost-effective use of NHS resources.