T Collier

Nurse-coordinated multidisciplinary, family-based cardiovascular disease prevention programme (EUROACTION) for patients with coronary heart disease and asymptomatic individuals at high risk of cardiovascular disease: a paired, cluster-randomised controlled trial

BACKGROUND Our aim was to investigate whether a nurse-coordinated multidisciplinary, family-based preventive cardiology programme could improve standards of preventive care in routine clinical practice. METHODS In a matched, cluster-randomised, controlled trial in eight European countries, six pairs of hospitals and six pairs of general practices were assigned to an intervention programme (INT) or usual care (UC) for patients with coronary heart disease or those at high risk of developing cardiovascular disease. The primary endpoints-measured at 1 year-were family-based lifestyle change; management of blood pressure, lipids, and blood glucose to target concentrations; and prescription of cardioprotective drugs. Analysis was by intention to treat. The trial is registered as ISRCTN 71715857. FINDINGS 1589 and 1499 patients with coronary heart disease in hospitals and 1189 and 1128 at high risk were assigned to INT and UC, respectively. In patients with coronary heart disease who smoked in the month before the event, 136 (58%) in the INT and 154 (47%) in the UC groups did not smoke 1 year afterwards (difference in change 10.4%, 95% CI -0.3 to 21.2, p=0.06). Reduced consumption of saturated fat (196 [55%] vs 168 [40%]; 17.3%, 6.4 to 28.2, p=0.009), and increased consumption of fruit and vegetables (680 [72%] vs 349 [35%]; 37.3%, 18.1 to 56.5, p=0.004), and oily fish (156 [17%] vs 81 [8%]; 8.9%, 0.3 to 17.5, p=0.04) at 1 year were greatest in the INT group. High-risk individuals and partners showed changes only for fruit and vegetables (p=0.005). Blood-pressure target of less than 140/90 mm Hg was attained by both coronary (615 [65%] vs 547 [55%]; 10.4%, 0.6 to 20.2, p=0.04) and high-risk (586 [58%] vs 407 [41%]; 16.9%, 2.0 to 31.8, p=0.03) patients in the INT groups. Achievement of total cholesterol of less than 5 mmol/L did not differ between groups, but in high-risk patients the difference in change from baseline to 1 year was 12.7% (2.4 to 23.0, p=0.02) in favour of INT. In the hospital group, prescriptions for statins were higher in the INT group (810 [86%] vs 794 [80%]; 6.0%, -0.5 to 11.5, p=0.04). In general practices in the intervention groups, angiotensin-converting enzyme inhibitors (297 [29%] INT vs 196 [20%] UC; 8.5%, 1.8 to 15.2, p=0.02) and statins (381 [37%] INT vs 232 [22%] UC; 14.6%, 2.5 to 26.7, p=0.03) were more frequently prescribed. INTERPRETATION To achieve the potential for cardiovascular prevention, we need local preventive cardiology programmes adapted to individual countries, which are accessible by all hospitals and general practices caring for coronary and high-risk patients.

Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.

BACKGROUND In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. METHODS In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. RESULTS The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users. INTERPRETATION These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. FUNDING Pfizer, Servier Research Group, and Leo Laboratories.

Hazardous alcohol consumption is a major factor in male premature mortality in a typical Russian city: prospective cohort study 2003-2009.

Introduction Russia has experienced massive fluctuations in mortality at working ages over the past three decades. Routine data analyses suggest that these are largely driven by fluctuations in heavy alcohol drinking. However, individual-level evidence supporting alcohol having a major role in Russian mortality comes from only two case-control studies, which could be subject to serious biases due to their design. Methods and Findings A prospective study of mortality (2003–9) of 2000 men aged 25–54 years at recruitment was conducted in the city of Izhevsk, Russia. This cohort was free from key limitations inherent in the design of the two earlier case-control studies. Cox proportional hazards regression was used to estimate hazard ratios of all-cause mortality by alcohol drinking type as reported by a proxy informant. Hazardous drinkers were defined as those who either drank non-beverage alcohols or were reported to regularly have hangovers or other behaviours related to heavy drinking episodes. Over the follow-up period 113 men died. Compared to non-hazardous drinkers and abstainers, men who drank hazardously had appreciably higher mortality (HR = 3.4, 95% CI 2.2, 5.1) adjusted for age, smoking and education. The population attributable risk percent (PAR%) for hazardous drinking was 26% (95% CI 14,37). However, larger effects were seen in the first two years of follow-up, with a HR of 4.6 (2.5, 8.2) and a corresponding PAR% of 37% (17, 51). Interpretation This prospective cohort study strengthens the evidence that hazardous alcohol consumption has been a major determinant of mortality among working age men in a typical Russian city. As such the similar findings of the previous case-control studies cannot be explained as artefacts of limitations of their design. As Russia struggles to raise life expectancy, which even in 2009 was only 62 years among men, control of hazardous drinking must remain a top public health priority.

Socio-Demographic Patterning of Physical Activity across Migrant Groups in India: Results from the Indian Migration Study

Objective To investigate the relationship between rural to urban migration and physical activity (PA) in India. Methods 6,447 (42% women) participants comprising 2077 rural, 2,094 migrants and 2,276 urban were recruited. Total activity (MET hr/day), activity intensity (min/day), PA Level (PAL) television viewing and sleeping (min/day) were estimated and associations with migrant status examined, adjusting for the sib-pair design, age, site, occupation, education, and socio-economic position (SEP). Results Total activity was highest in rural men whereas migrant and urban men had broadly similar activity levels (p<0.001). Women showed similar patterns, but slightly lower levels of total activity. Sedentary behaviour and television viewing were lower in rural residents and similar in migrant and urban groups. Sleep duration was highest in the rural group and lowest in urban non-migrants. Migrant men had considerably lower odds of being in the highest quartile of total activity than rural men, a finding that persisted after adjustment for age, SEP and education (OR 0.53, 95% CI 0.37, 0.74). For women, odds ratios attenuated and associations were removed after adjusting for age, SEP and education. Conclusion Our findings suggest that migrants have already acquired PA levels that closely resemble long-term urban residents. Effective public health interventions to increase PA are needed.

The incidence and importance of anaemia in patients undergoing cardiac surgery in the UK – the first Association of Cardiothoracic Anaesthetists national audit†

The importance and variability of pre‐operative anaemia in cardiac surgical patients across the UK is not known, and there is debate about its association with patient outcomes. The Association of Cardiothoracic Anaesthetists carried out its first national audit on anaemia and transfusion, and analysed data from 19,033 patients operated on in 12 cardiac surgical centres between 2010 and 2012; 5895 (31%) had pre‐operative anaemia. Centre‐specific prevalence of anaemia varied from 23% to 45%; anaemia was associated with older patients, diabetes and surgical risk (EuroSCORE). Nevertheless, controlling for these factors, regional variation remained an independent effect (p < 0.001). Multivariable analysis demonstrated an independent association of anaemia with transfusion (odds ratio (95% confidence interval) 2.75 (2.55–2.95), p < 0.001), mortality (1.42 (1.18–1.71), p < 0.001) and hospital stay (geometric mean ratio (95% confidence interval) 1.15 (1.13–1.17), p < 0.001). Haemoglobin concentration per se was also independently associated with worse outcomes; a 10 g.l−1 decrease in haemoglobin was associated with a 43% increase (95% confidence interval 40–46%) in the odds of transfusion and a 16% increase (95% confidence interval 10–22%) in the odds of mortality (both p < 0.001). This large UK‐wide audit has demonstrated marked regional variation in both anaemia and transfusion, with a consistently high incidence of both. The independent association between pre‐operative anaemia and worse outcomes in UK practice has also been confirmed, and robust prospective study of anaemia treatment before cardiac surgery is required; these data will assist in designing such trials.

Evaluation of the Indian Migration Study Physical Activity Questionnaire (IMS-PAQ): a cross-sectional study

BackgroundSocio-cultural differences for country-specific activities are rarely addressed in physical activity questionnaires. We examined the reliability and validity of the Indian Migration Study Physical Activity Questionnaire (IMS-PAQ) in urban and rural groups in India.MethodsA sub-sample of IMS participants (n = 479) was used to examine short term (≤1 month [n = 158]) and long term (> 1 month [n = 321]) IMS-PAQ reliability for levels of total, sedentary, light and moderate/vigorous activity (MVPA) intensity using intraclass correlation (ICC) and kappa coefficients (k). Criterion validity (n = 157) was examined by comparing the IMS-PAQ to a uniaxial accelerometer (ACC) worn ≥4 days, via Spearmans rank correlations (ρ) and k, using Bland-Altman plots to check for systematic bias. Construct validity (n = 7,000) was established using linear regression, comparing IMS-PAQ against theoretical constructs associated with physical activity (PA): BMI [kg/m2], percent body fat and pulse rate.ResultsIMS-PAQ reliability ranged from ICC 0.42-0.88 and k = 0.37-0.61 (≤1 month) and ICC 0.26 to 0.62; kappa 0.17 to 0.45 (> 1 month). Criterion validity was ρ = 0.18-0.48; k = 0.08-0.34. Light activity was underestimated and MVPA consistently and substantially overestimated for the IMS-PAQ vs. the accelerometer. Criterion validity was moderate for total activity and MVPA. Reliability and validity were comparable for urban and rural participants but lower in women than men. Increasing time spent in total activity or MVPA, and decreasing time in sedentary activity were associated with decreasing BMI, percent body fat and pulse rate, thereby demonstrating construct validity.ConclusionIMS-PAQ reliability and validity is similar to comparable self-reported instruments. It is an appropriate tool for ranking PA of individuals in India. Some refinements may be required for sedentary populations and women in India.

Making Sense of Statistics in Clinical Trial Reports: Part 1 of a 4-Part Series on Statistics for Clinical Trials

This paper is a practical guide to the essentials of statistical analysis and reporting of randomized clinical trials (RCTs). It is the first in a series of 4 educational papers on statistical issues for RCTs, which will also include statistical controversies in RCT reporting and interpretation, the fundamentals of design for RCTs, and statistical challenges in the design and monitoring of RCTs. Here, we concentrate on displaying results in tables and figures, estimating treatment effects, expressing uncertainty using confidence intervals, and using p values wisely to assess the strength of evidence for a treatment difference. The various methods and their interpretation are illustrated by recent, topical cardiology trial results.

Erratum to: PREVENTT: preoperative intravenous iron to treat anaemia in major surgery: study protocol for a randomised controlled trial.

Anaemia is common in patients undergoing major surgery. The current standard of care for patients with low haemoglobin in the peri-operative period is blood transfusion. The presence of preoperative anaemia is associated with an increased likelihood of the patient receiving peri-operative transfusion and worsened outcomes following surgery, more post-operative complications, delayed recovery and greater length of hospital stay. Intravenous iron, if applied in the preoperative setting, may correct anaemia by the time of surgery and reduce the need for blood transfusion and improve outcomes.

Clinical benefits of eplerenone in patients with systolic heart failure and mild symptoms when initiated shortly after hospital discharge: analysis from the EMPHASIS-HF trial

AIMS Cardiovascular hospitalization (CVH) in patients with heart failure (HF) is associated with a high post-discharge rate of early re-admission and CV death. Eplerenone might be effective in reducing the incidence of these adverse clinical outcomes during this period. METHODS AND RESULTS The EMPHASIS-HF trial compared eplerenone with placebo added to standard therapy in 2737 patients with New York Heart Association class II HF and left ventricular ejection fraction ≤35%. We conducted a post hoc analysis in the 2338 patients randomized within 180 days of a CVH. The interaction between the time from the qualifying CVH to randomization and the primary outcome of CV death or hospitalization for HF (HHF), as well as other secondary outcomes, was assessed in Cox survival models. Most of the qualifying CVHs were HHF (N = 1496, 64.0%), acute coronary syndromes (N = 390, 16.7%), and arrhythmias (N = 197, 7.2%). The median time of study drug initiation from qualifying CVH was 42 days. The relative rate reductions in CV death/HHF, HHF, and all-cause mortality were similar (P for interaction = 0.65, 0.44, and 0.40, respectively) whether the treatment was initiated <42 or 42+ days after qualifying CVH. Absolute rate reductions were -5.61 [-8.67, -2.55] events per 100 patient × years in the <42 days group and -3.58 [-6.37, -0.79] in the 42+ days group. The adverse effects of eplerenone were also unaffected by the time from the qualifying CVH. CONCLUSION Eplerenone is safe, improves survival, and may prevent re-admission when initiated soon after a hospitalization for HF or acute coronary syndromes in patients with systolic HF and mild symptoms.

The Present and FutureState-of-the-Art ReviewStatistical Controversies in Reporting of Clinical Trials: Part 2 of a 4-Part Series on Statistics for Clinical Trials

This paper tackles several statistical controversies that are commonly faced when reporting a major clinical trial. Topics covered include: multiplicity of data, interpreting secondary endpoints and composite endpoints, the value of covariate adjustment, the traumas of subgroup analysis, assessing individual benefits and risks, alternatives to analysis by intention to treat, interpreting surprise findings (good and bad), and the overall quality of clinical trial reports. All is put in the context of topical cardiology trial examples and is geared to help trialists steer a wise course in their statistical reporting, thereby giving readers a balanced account of trial findings.