Neeraj Bhala

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.

Searching As reported in the study protocol (see Other Publications of Related Interest), potentially eligible studies were identified prospectively by computer-aided literature searches, manual searches of journals, examination of reference lists of trials and review articles, examination of abstracts and conference proceedings, by collaboration with the trial register of the International Committee on Thrombosis and Haemostasis and by contacting colleagues, collaborators and drug manufacturers.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials

Summary Background The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14–1·66; p=0·0009) or diclofenac (1·41, 1·12–1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31–2·37; p=0·0001; diclofenac 1·70, 1·19–2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10–4·48; p=0·0253), but not major vascular events (1·44, 0·89–2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69–1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56–6·41; p=0·17), but not by naproxen (1·08, 0·48–2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17–2·81, p=0·0070; diclofenac 1·89, 1·16–3·09, p=0·0106; ibuprofen 3·97, 2·22–7·10, p<0·0001; and naproxen 4·22, 2·71–6·56, p<0·0001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. Funding UK Medical Research Council and British Heart Foundation.

The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013

BACKGROUND With recent improvements in vaccines and treatments against viral hepatitis, an improved understanding of the burden of viral hepatitis is needed to inform global intervention strategies. We used data from the Global Burden of Disease (GBD) Study to estimate morbidity and mortality for acute viral hepatitis, and for cirrhosis and liver cancer caused by viral hepatitis, by age, sex, and country from 1990 to 2013. METHODS We estimated mortality using natural history models for acute hepatitis infections and GBDs cause-of-death ensemble model for cirrhosis and liver cancer. We used meta-regression to estimate total cirrhosis and total liver cancer prevalence, as well as the proportion of cirrhosis and liver cancer attributable to each cause. We then estimated cause-specific prevalence as the product of the total prevalence and the proportion attributable to a specific cause. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs). FINDINGS Between 1990 and 2013, global viral hepatitis deaths increased from 0·89 million (95% uncertainty interval [UI] 0·86-0·94) to 1·45 million (1·38-1·54); YLLs from 31·0 million (29·6-32·6) to 41·6 million (39·1-44·7); YLDs from 0·65 million (0·45-0·89) to 0·87 million (0·61-1·18); and DALYs from 31·7 million (30·2-33·3) to 42·5 million (39·9-45·6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990. INTERPRETATION Viral hepatitis is a leading cause of death and disability worldwide. Unlike most communicable diseases, the absolute burden and relative rank of viral hepatitis increased between 1990 and 2013. The enormous health loss attributable to viral hepatitis, and the availability of effective vaccines and treatments, suggests an important opportunity to improve public health. FUNDING Bill & Melinda Gates Foundation.

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy.

Background Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials. Methods and Findings Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]). Conclusions In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).

Measuring progress on NCDs: one goal and five targets

Heads of states and governments made commitments to the prevention and control of non-communicable diseases (NCDs) in the Political Declaration from the UN High-Level Meeting on NCDs in September, 2011. A key commitment in the Political Declaration calls upon WHO to develop a comprehensive global monitoring framework to assess progress in the implementation of national strategies and plans for the four main NCDs: cardiovascular diseases (CVD), diabetes, cancer, and chronic respiratory diseases. Central to the monitoring framework is the selection of goals and targets for NCDs. WHO member states have agreed on an NCD target of a 25% reduction by 2025 in the probability of dying from the four main NCDs for people aged 30–70 years. We refer to this target as the overarching NCD goal (“25 by 25”). The latest WHO proposals include ten targets to reach this goal. Although these targets address important areas of NCD prevention, the choice and hierarchy of the ten targets is based on their level of support by member states. There is strong support from member states for targets on raised blood pressure, tobacco smoking, salt intake, and physical inactivity. Targets deemed as “requiring further development” relate to obesity, fat intake, alcohol consumption, raised total cholesterol, the availability of essential generic NCD medicines and basic technologies to treat major NCDs, and drug therapy to prevent heart attacks and strokes. Member states will discuss these proposed targets at a consultation in November, 2012, and the monitoring framework will be finalised at the World Health Assembly in May, 2013. In our view, the key criteria for choosing any target should be that it has a strong scientific basis, is sensitive to change, and that achieving it will have a major impact on the global NCD mortality goal. Other criteria include empirical evidence that the target is achievable with cost-effective interventions that are feasible for scaling up, and that baseline data and robust methods for assessing progress are available. Unlike WHO, we propose that implementation of interventions should initially be limited to only a small number of priority targets to ensure that existing resources are used most efficiently, with additional targets added as country experience and success builds. In proposing targets, we underline technical considerations over political consensus. Further, to promote equity, the targets must be reported in relation to measures of socioeconomic status, for example, education, and gender. Based on earlier work undertaken with WHO, we propose five priority targets to meet the NCD mortality goal by 2025, with 2010 as the baseline (figure). The priority targets include two of the main risk factors for NCDs—tobacco use and salt reduction (as the key dietary target)—and one treatment target. Physical inactivity and alcohol reduction have been included because they are the other two main risk factors for NCDs highlighted in the Political Declaration. Tobacco control is the key NCD target and is relevant for the prevention of a wide range of NCDs. The current global prevalence of tobacco smoking is about 23%, with major variations by country and gender. We propose a 40% relative reduction in prevalence of tobacco use, including smokeless tobacco, by 2025; this target would achieve a global adult smoking prevalence of about 14%. The required rate of change has already been reached in several countries, including middle-income countries such as Uruguay. Achievement of this target requires accelerated implementation of all elements of the WHO Framework Convention on Tobacco Control. Some countries have committed to being tobacco free by 2025. An even longer-term global goal is for a tobacco free world by 2040, with a prevalence of adult tobacco use of less than 5%. The key dietary target is a reduction in population levels of salt consumption to reduce population blood pressure. The target for 2025 is to achieve the WHO target of 5 g of salt intake per adult per day; the current global daily salt intake is about 9–12 g of salt per adult.

Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials

A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.

Changing trends of diseases in Eastern Europe: Closing the gap

One of the greatest challenges in Europe at the beginning of the 21st Century is the wide east-west health gap. In 2008, the difference in life expectancy between men in some Western European countries and Russia was 20 years. Whilst trends for life expectancy at birth have improved in many areas around the world, those for Russia, as well as those for some other former Soviet Union countries, have fluctuated greatly and have not shown signs of growth since the middle of the 20th Century. This problem is most acute in Russia and former Soviet Union countries, but is also far from being solved in the states that have made significant progress since 1990 and joined the European Union in the 21st Century. One of the priorities of the Polish presidency of the European Union, which began in July 2011, is the call for a European solidarity for health that could help to close the health gap dividing Europe.

Incidence of gastrointestinal cancers by ethnic group in England, 2001–2007

Objective To compare the incidence of six gastrointestinal cancers (colorectal, oesophageal, gastric, liver, gallbladder and pancreatic) among the six main ‘non-White’ ethnic groups in England (Indian, Pakistani, Bangladeshi, Black African, Black Caribbean and Chinese) to each other and to Whites. Methods We analysed all 378 511 gastrointestinal cancer registrations from 2001–2007 in England. Ethnicity was obtained by linkage to the Hospital Episodes Statistics database and we used mid-year population estimates from 2001–2007. Incidence rate ratios adjusted for age, sex and income were calculated, comparing the six ethnic groups (and combined ‘South Asian’ and ‘Black’ groups) to Whites and to each other. Results There were significant differences in the incidence of all six cancers between the ethnic groups (all p<0.001). In general, the ‘non-White’ groups had a lower incidence of colorectal, oesophageal and pancreatic cancer compared to Whites and a higher incidence of liver and gallbladder cancer. Gastric cancer incidence was lower in South Asians but higher in Blacks and Chinese. There was strong evidence of differences in risk between Indians, Pakistanis and Bangladeshis for cancer of the oesophagus, stomach, liver and gallbladder (all p<0.001) and between Black Africans and Black Caribbeans for liver and gallbladder cancer (both p<0.001). Conclusions The risk of gastrointestinal cancers varies greatly by individual ethnic group, including within those groups that have traditionally been grouped together (South Asians and Blacks). Many of these differences are not readily explained by known risk factors and suggest that important, potentially modifiable causes of these cancers are still to be discovered.

Systematic review with meta‐analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection

Clostridium difficile infection (CDI) is the commonest nosocomial cause of diarrhoea. Faecal microbiota transplantation (FMT) is an approved treatment for recurrent or refractory CDI but there is uncertainty about its use.

Iron treatment and inflammatory bowel disease: What happens in real practice?

BACKGROUND AND AIMS Iron deficiency anaemia (IDA), the most common extra-intestinal complication of inflammatory bowel disease (IBD), negatively impacts quality of life. We audited the recent practice of anaemia treatment in an unselected IBD population. METHODS A questionnaire was distributed to adult IBD outpatients in a university hospital to assess the form and frequency of iron prescribed, duration of use, side effects, and completion of therapy. The efficacy of treatment was determined by the resolution of anaemia and change in haemoglobin from baseline. RESULTS Of 87 IBD patients (60 patients with Crohns disease, 25 with ulcerative colitis, 2 with microscopic colitis), 85 received various dosing regimens of iron tablets; 15 patients also received IV iron. Side effects were reported in 43 (51%) patients, with no clear relationship to dose prescribed and 26 (32%) patients were unable to complete the intended course. Only 36 (42%) patients completed the course of oral iron without side effects and in these patients, haemoglobin normalised in about 30%. Their median haemoglobin change was 12.5 (5.3-23.5)g/l. The median duration of treatment in those without side effects was 4.5months, and in those with adverse effects was 2months. Only one adverse effect was reported for IV iron. CONCLUSIONS Treatment with oral iron results in failure to control anaemia in 2 out of 3 IBD patients, which is likely in part to be due to the side effects reported by over half of patients. Patients failing to tolerate or adequately respond to therapy should be offered alternative treatment.