Huseyin Naci

Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study

Objective To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes. Design Metaepidemiological study. Eligibility criteria Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care). Data sources Medline and Cochrane Database of Systematic Reviews, May 2013. Main outcome measure Mortality. Data synthesis We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis. Results We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339 274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14 716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise v anticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11, 1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant. Conclusions Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.

Distribution of road traffic deaths by road user group: a global comparison

Background: Road traffic deaths are a major global health and development problem. An understanding of the existing burden of road traffic deaths in the population is necessary for developing effective interventions. Objective: To outline systematically the global distribution of road traffic deaths by road user groups (pedestrians, bicyclists, motorcyclists, motorised four-wheeler occupants). Methods: Comprehensive searches of PubMed, Google, Google Scholar, TransportLink, grey literature and reference lists and communication with experts from international organisations and country-level institutions were conducted to identify eligible studies and data sources. All data sources that provided a breakdown of road traffic deaths by road user group at the national or sub-national level were eligible for inclusion. A breakdown of road traffic deaths by road user group was constructed for 14 epidemiologically defined World Health Organization (WHO) sub-regions in addition to World Bank income categories. In addition, the total number of road traffic fatalities by road user group in low-income, middle-income and high-income countries was estimated. Results: The breakdown of road traffic deaths by road user group varies dramatically across epidemiological WHO sub-regions. The magnitude of pedestrian fatalities ranges from more than half in African sub-region AfrE (55%) to 15% or less in AmrA or EurA. The distribution also varies across low-income, middle-income and high-income countries. 45% of road traffic fatalities in low-income countries are among pedestrians, whereas an estimated 29% in middle-income and 18% in high-income countries are among pedestrians. The burden of road traffic injuries on vulnerable road users differs substantially across income levels. An estimated total of 227 835 pedestrians die in low-income countries, as opposed to 161 501 in middle-income countries and 22 500 in high-income countries each year. Conclusions: Ameliorating road safety requires the implementation of context-specific solutions. This review of the road traffic injury literature provides strong evidence that the distribution of road traffic fatalities varies dramatically across different parts of the world. Therefore, context-appropriate and effective prevention strategies that protect the particular at-risk road user groups should be carefully investigated.

Is network meta-analysis as valid as standard pairwise meta-analysis? It all depends on the distribution of effect modifiers

BackgroundIn the last decade, network meta-analysis of randomized controlled trials has been introduced as an extension of pairwise meta-analysis. The advantage of network meta-analysis over standard pairwise meta-analysis is that it facilitates indirect comparisons of multiple interventions that have not been studied in a head-to-head fashion. Although assumptions underlying pairwise meta-analyses are well understood, those concerning network meta-analyses are perceived to be more complex and prone to misinterpretation.DiscussionIn this paper, we aim to provide a basic explanation when network meta-analysis is as valid as pairwise meta-analysis. We focus on the primary role of effect modifiers, which are study and patient characteristics associated with treatment effects. Because network meta-analysis includes different trials comparing different interventions, the distribution of effect modifiers cannot only vary across studies for a particular comparison (as with standard pairwise meta-analysis, causing heterogeneity), but also between comparisons (causing inconsistency). If there is an imbalance in the distribution of effect modifiers between different types of direct comparisons, the related indirect comparisons will be biased. If it can be assumed that this is not the case, network meta-analysis is as valid as pairwise meta-analysis.SummaryThe validity of network meta-analysis is based on the underlying assumption that there is no imbalance in the distribution of effect modifiers across the different types of direct treatment comparisons, regardless of the structure of the evidence network.

Comparative Tolerability and Harms of Individual Statins A Study-Level Network Meta-Analysis of 246 955 Participants From 135 Randomized, Controlled Trials

Background—Our objective was to estimate the comparative harms of individual statins using both placebo-controlled and active-comparator trials. Methods and Results—We systematically reviewed randomized trials evaluating different statins in participants with and without cardiovascular disease. We performed random-effects pairwise and network meta-analyses to quantify the relative harms of individual statins. We included 55 two-armed placebo-controlled and 80 two- or multiarmed active-comparator trials including 246 955 individuals. According to pairwise meta-analyses, individual statins were not different than control in terms of myalgia, creatine kinase elevation, cancer, and discontinuations because of adverse events. Statins as a class resulted in significantly higher odds of diabetes mellitus (odds ratio, 1.09; 95% confidence interval, 1.02–1.16) and transaminase elevations (odds ratio, 1.51; 95% confidence interval, 1.24–1.84) compared with control. When individual statins were compared in network meta-analyses, there were numerous statistically detectable differences, favoring simvastatin and pravastatin. According to dose-level comparisons, individual statins resulted in higher odds of discontinuations with higher doses of atorvastatin and rosuvastatin. Similarly, higher doses of atorvasatin, fluvastatin, lovastatin, and simvastatin were associated with higher odds of transaminase elevations. Simvastatin at its highest doses was associated with creatine kinase elevations (odds ratio, 4.14; 95% credible interval, 1.08–16.24). Meta-regression analyses adjusting for study-level age at baseline, low-density lipoprotein cholesterol level, and publication year did not explain heterogeneity. There was no detectable inconsistency in the network. Conclusions—As a class, adverse events associated with statin therapy are not common. Statins are not associated with cancer risk but do result in a higher odds of diabetes mellitus. Among individual statins, simvastatin and pravastatin seem safer and more tolerable than other statins.

Economic Burden of Multiple Sclerosis: A Systematic Review of the Literature

Multiple sclerosis (MS) is a disease of the CNS, typically striking adults during the primary productive time of their life. The symptoms of MS can restrict the individual’s physical activity and income-earning ability, resulting in a major financial burden on the patient, family, health system and society. This systematic literature review was conducted to document the economic burden of MS.Employing pre-defined search terms and inclusion/exclusion criteria, systematic searches were conducted in MEDLINE, EMBASE, PsycINFO, the Health Economic Evaluations Database (HEED), the NHS Economic Evaluation Database (EED) and the UK National Institute for Health and Clinical Excellence (NICE) website as well as conference abstracts.We identified 29 cost-of-illness studies that met the a priori inclusion criteria. The cost categories responsible for the majority of costs associated with MS varied across countries. There was a significant increase in costs associated with an increase in disease severity as measured by the Kurtzke Expanded Disability Status Scale (EDSS) score. The increase in magnitude was coupled with changes in the distribution of costs; although direct medical costs were important contributors in earlier stages of disease, they were outweighed by indirect costs in later stages, mainly due to relapses and productivity losses.Considering the increased costs associated with relapse occurrence and increasing disease severity, pharmaceutical or non-pharmaceutical interventions aimed at delaying the progression of disease may help to reduce the economic burden of MS.

Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials.

Background The extent to which individual statins vary in terms of clinical outcomes across all populations, in addition to secondary and primary prevention has not been studied extensively in meta-analyses. Methods We systematically studied 199,721 participants in 92 placebo-controlled and active-comparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into account the dose differences across trials. Systematic review registration: PROSPERO 2011:CRD42011001470. Results There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. No trial directly compared all six statins to each other. Across all populations, statins were significantly more effective than control in reducing all-cause mortality (OR 0.87, 95% credible interval 0.82–0.92) and major coronary events (OR 0.69, 95% CI 0.64–0.75). In terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.48–0.94) and fluvastatin (OR 0.59, 95% CI 0.36–0.95) were significantly more effective than rosuvastatin at comparable doses. In participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.75–0.90) and major coronary events (OR 0.69, 95% CI 0.62–0.77). Atorvastatin was significantly more effective than pravastatin (OR 0.65, 95% CI 0.43–0.99) and simvastatin (OR 0.68, 95% CI 0.38–0.98) for secondary prevention of major coronary events. In primary prevention, statins significantly reduced deaths (OR 0.91, 95% CI 0.83–0.99) and major coronary events (OR 0.69, 95% CI 0.61–0.79) with no differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and simvastatin (62%) had the highest overall probability of being the best treatment in terms of both outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant differences in preventing major coronary events compared with other statins. No significant heterogeneity or inconsistency was detected. Conclusions Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention. This analysis provides evidence for potential differences between individual statins, which are not fully explained by their low-density lipoprotein cholesterol-reducing effects. The observed differences between statins should be investigated in future prospective studies.

From "retailers" to health care providers : Transforming the role of community pharmacists in chronic disease management

Community pharmacists are the third largest healthcare professional group in the world after physicians and nurses. Despite their considerable training, community pharmacists are the only health professionals who are not primarily rewarded for delivering health care and hence are under-utilized as public health professionals. An emerging consensus among academics, professional organizations, and policymakers is that community pharmacists, who work outside of hospital settings, should adopt an expanded role in order to contribute to the safe, effective, and efficient use of drugs-particularly when caring for people with multiple chronic conditions. Community pharmacists could help to improve health by reducing drug-related adverse events and promoting better medication adherence, which in turn may help in reducing unnecessary provider visits, hospitalizations, and readmissions while strengthening integrated primary care delivery across the health system. This paper reviews recent strategies to expand the role of community pharmacists in Australia, Canada, England, the Netherlands, Scotland, and the United States. The developments achieved or under way in these countries carry lessons for policymakers world-wide, where progress thus far in expanding the role of community pharmacists has been more limited. Future policies should focus on effectively integrating community pharmacists into primary care; developing a shared vision for different levels of pharmacist services; and devising new incentive mechanisms for improving quality and outcomes.

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

Expanding the role of community pharmacists: Policymaking in the absence of policy-relevant evidence?

BACKGROUND AND OBJECTIVES Policies to expand the traditional role of community pharmacists have been implemented or at least considered in a number of countries, as advocated by academics, professional organizations, and governments. Such reforms come on the heel of pressing system-wide challenges. At a time of growing interest in evidence-based policymaking, what is the policy-relevant evidence base in support of this new expanded role for community pharmacists? METHODS An umbrella review was conducted to identify published systematic reviews of evidence on the effectiveness of community pharmacist interventions. Findings of the identified reviews were documented according to Pharmaceutical Care and Total Pharmacy Care models, and evaluated on the basis of internal and external validity. The internal validity of identified reviews was evaluated in terms of the comparability of populations, interventions, and outcomes. External validity was based on the reproducibility and generalizability of review findings. RESULTS Thirty-three systematic reviews published since 2000 evaluated the evidentiary support for the expanded role of community pharmacists, which focuses on two primary objectives: (1) to encourage the effective, safe and appropriate use of medicines and (2) to promote the prevention and management of chronic diseases. The results of most systematic reviews were mixed, with unclear policy relevance. Important methodological drawbacks were found in terms of study identification and selection, and comparability of interventions and outcomes. In addition, the external validity of the findings was inconclusive on the basis of reproducibility and generalizability. CONCLUSIONS There is inconclusive evidence in support of expanding the role of community pharmacists. This raises an important question: should the pharmacy profession only undertake tasks for which there is strong policy relevance with evidence of economic and public health benefits? In spite of this tension between the necessity to formulate new policies during a period of economic constraints and the level of corresponding evidence, several countries have begun entertaining policies to equip community pharmacists with patient-centered responsibilities. As implementing such expanded roles requires significant changes in the wider health care system, further research is needed to evaluate country-level policy developments.

Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials

Aims The extent to which individual statins vary in terms of their impact on serum lipid levels has been studied mainly on the basis of placebo-controlled trials. Our objective was to review and quantify the dose-comparative effects of different statins on serum lipid levels using both placebo- and active-comparator trials. Methods We systematically reviewed randomized trials evaluating different statins in participants with, or at risk of developing, cardiovascular disease. We performed random-effects Bayesian network meta-analyses to quantify the the relative potency of individual statins across all possible dose combinations using both direct and indirect evidence. Dose-comparative effects were determined by estimating the mean change from baseline in serum lipids as compared to control treatment. (systematic review registration: PROSPERO 2011:CRD42011001470). Results We included 181 placebo-controlled and active-comparator trials including 256,827 individuals. There were 83 two-armed placebo-controlled trials and the remaining 98 were two- or multi-armed active-comparator trials. All statins reduced serum LDL and total cholesterol levels: higher doses resulted in higher reductions in pretreatment LDL and total cholesterol concentrations. In absolute terms, all statins significantly reduced LDL cholesterol levels as compared to control treatment from average baseline levels of approximately 150 mg/dl, except for fluvastatin at ≤20 mg/day and lovastatin at ≤10 mg/day. Atorvastatin, rosuvastatin, and simvastatin were broadly equivalent in terms of their LDL cholesterol-lowering effects. Dose-comparative effects of indivudual statins were not different between those with and without coronary heart disease at baseline. According to meta-regression analyses, LDL cholesterol-lowering effects of individual statins were not impacted by differences across trials in terms of baseline mean age and proportion of women as trial participants. Pretreatment LDL cholesterol concentrations had a marginally statistically significant effect on LDL cholesterol change from baseline. Mean differences from baseline in HDL cholesterol as compared to control treatment was not significant for any statin-dose combination. Conclusions The findings of this comprehensive review provide supporting evidence for the dose–response relationship of statins in reducing LDL and total cholesterol. The LDL cholesterol-reducing effects of some statins appear less pronounced than the findings of previous meta-analyses, which is particularly the case for the high-dose formulations of atorvastatin and rosuvastatin. The most consistent evidence for a combined reduction in both LDL and total cholesterol was achieved with atorvastatin at >40 mg/day, rosuvastatin at >10 mg/day, and simvastatin at >40 mg/day, which appear equivalent in terms of their LDL and total cholesterol-reducing effects.