Cardiovascular risk factors and the risk of major adverse limb events in patients with symptomatic cardiovascular disease.

AIM: To determine the relationship between non-high-density lipoprotein cholesterol (non-HDL-c), systolic blood pressure (SBP) and smoking and the risk of major adverse limb events (MALE) and the combination with major adverse cardiovascular events (MALE/MACE) in patients with symptomatic vascular disease. METHODS: Patients with symptomatic vascular disease from the Utrecht Cardiovascular Cohort - Secondary Manifestations of ARTerial disease (1996-2017) study were included. The effects of non-HDL-c, SBP and smoking on the risk of MALE were analysed with Cox proportional hazard models stratified for presence of peripheral artery disease (PAD). MALE was defined as major amputation, peripheral revascularisation or thrombolysis in the lower limb. RESULTS: In 8139 patients (median follow-up 7.8 years, IQR 4.0-11.8), 577 MALE (8.7 per 1000 person-years) and 1933 MALE/MACE were observed (29.1 per 1000 person-years). In patients with PAD there was no relation between non-HDL-c and MALE, and in patients with coronary artery disease (CAD), cerebrovascular disease (CVD) or abdominal aortic aneurysm (AAA) the risk of MALE was higher per 1 mmol/L non-HDL-c (HR 1.14, 95% CI 1.01 to 1.29). Per 10 mm Hg SBP, the risk of MALE was higher in patients with PAD (HR 1.06, 95% CI 1.01 to 1.12) and in patients with CVD/CAD/AAA (HR 1.15, 95% CI 1.08 to 1.22). The risk of MALE was higher in smokers with PAD (HR 1.45, 95% CI 0.97 to 2.14) and CAD/CVD/AAA (HR 7.08, 95% CI 3.99 to 12.57). CONCLUSIONS: The risk of MALE and MALE/MACE in patients with symptomatic vascular disease differs according to vascular disease location and is associated with non-HDL-c, SBP and smoking. These findings confirm the importance of MALE as an outcome and underline the importance of risk factor management in patients with vascular disease.

Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease.

OBJECTIVE: In statin-treated patients with stable coronary artery disease (CAD), residual risk of cardiovascular events is partly explained by plasma levels of low-density lipoprotein cholesterol (LDL-C). This study aimed to estimate individual benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in CAD patients already treated with high-dose statin. METHODS: Individual lifetime benefit was estimated in months gain free of stroke or myocardial infarction (MI) until age 80 years. Predictions were based on two competing risk models developed in data from 4853 patients with CAD originating from the atorvastatin 80 mg arm of the Treating to New Targets (TNT) trial. The relative effect of PCSK9 inhibition was added to the models and was assumed based on average estimates from large clinical trials. We accounted for individual LDL-C levels, assuming 50% LDL-C reduction by PCSK9 inhibition and 21% cardiovascular risk reduction per mmol/L (39 mg/dL) LDL-C lowering. RESULTS: Estimated individual gain was <6 months in 61% of the patients, 6-12 months in 28% of the patients and ≥12 months in 10% of the patients (median 5, quartiles 2-8 months). Highest estimated benefit was observed in younger patients (aged 40-60 years) with high risk factor burden, particularly if LDL-C levels were >1.8 mmol/L (>70 mg/dL). Estimated benefit was lowest (≤5 months) in older patients (≥70 years), in particular if LDL-C and other risk factors levels were low. CONCLUSION: The individual estimated lifetime benefit from PCSK9 inhibition in patients with stable CAD on high-dose statin varied from <6 to ≥12 months free of stroke or MI. Highest benefit is expected in younger patients (age 40-60 years) with high risk factor burden and relatively high LDL-C levels. TRIAL REGISTRATION NUMBER: NCT00327691; Post-results.

Complex interventions for preventing diabetic foot ulceration.

BACKGROUND: Ulceration of the feet, which can lead to the amputation of feet and legs, is a major problem for people with diabetes mellitus, and can cause substantial economic burden. Single preventive strategies have not been shown to reduce the incidence of foot ulceration to a significant extent. Therefore, in clinical practice, preventive interventions directed at patients, healthcare providers and/or the structure of health care are often combined (complex interventions). OBJECTIVES: To assess the effectiveness of complex interventions in the prevention of foot ulcers in people with diabetes mellitus compared with single interventions, usual care or alternative complex interventions. A complex intervention is defined as an integrated care approach, combining two or more prevention strategies on at least two different levels of care: the patient, the healthcare provider and/or the structure of health care. SEARCH METHODS: For the second update we searched the Cochrane Wounds Group Specialised Register (searched 22 May 2015), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 4), The Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2015, Issue 4), The Health Technology Assessment Database (HTA) (The Cochrane Library 2015, Issue 4), The NHS Economic Evaluation Database (NHS EED) (The Cochrane Library 2015, Issue 4), Ovid MEDLINE (1946 to 22 May 2015), Ovid MEDLINE (In-Process & Other Non-Indexed Citations 21 May, 2015), Ovid EMBASE (1974 to 21 May, 2015) and EBSCO CINAHL (1982 to 22 May, 2015). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) which compared the effectiveness of combinations of preventive strategies, not solely patient education, for the prevention of foot ulcers in people with diabetes mellitus, with single interventions, usual care or alternative complex interventions. DATA COLLECTION AND ANALYSIS: Two review authors were assigned to independently select studies, to extract study data and to assess risk of bias of included studies, using predefined criteria. MAIN RESULTS: Only six RCTs met the criteria for inclusion. The study characteristics differed substantially in terms of healthcare settings, the nature of the interventions studied and outcome measures reported. In three studies that compared the effect of an education-centred complex intervention with usual care or written instructions, only little evidence of benefit was found. Three studies compared the effect of more intensive and comprehensive complex interventions with usual care. One study found a significant and cost-effective reduction, one of lower extremity amputations (RR 0.30, 95% CI 0.31 to 0.71). One other study found a significant reduction of both amputation and foot ulcers. The last study reported improvement of patients' self care behaviour. All six included RCTs were at high risk of bias, with hardly any of the predefined quality assessment criteria met. AUTHORS' CONCLUSIONS: There is no high-quality research evidence evaluating complex interventions for preventing diabetic foot ulceration and insufficient evidence of benefit.

Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women.

BACKGROUND: The value of aspirin in primary prevention of cancer and cardiovascular disease (CVD) remains unclear. The aim of this study was to identify women who benefit from alternate-day aspirin with regard to all relevant outcomes, including cancer, CVD and major gastrointestinal bleeding. METHODS: Long term follow-up data of 27 939 healthy women with baseline plasma samples in the Women's Health Study, a randomised trial of 100 mg alternate-day aspirin versus placebo, were used to develop competing risks models for individualised prediction of absolute risk reduction of the combination of CVD, cancer and major gastrointestinal bleeding by aspirin. RESULTS: Although aspirin was associated with a modestly decreased 15-year risk of colorectal cancer, CVD, and in some women non-colorectal cancer, aspirin treatment resulted in a negative treatment effect in the majority of women if gastrointestinal bleeding was also taken into account. The excess risk of major gastrointestinal bleeding by aspirin increased with age, but the benefits for colorectal cancer and CVD risk were also greater at higher age. Decision curves indicated that selective treatment of women ≥65 years may improve net benefit compared to treating all, none and prediction-based treatment. The observed 15-year number needed to treat to prevent one event among women ≥65 years was 29 (95% CI 12 to 102). CONCLUSIONS: Concurrent evaluation of the absolute effects on cancer, CVD and major gastrointestinal bleeding showed that alternate-day use of low-dose aspirin is ineffective or harmful in the majority of women in primary prevention. Selective treatment of women ≥65 years with aspirin may improve net benefit. TRIAL REGISTRATION NUMBER: NCT00000479.

Patient education for preventing diabetic foot ulceration.

BACKGROUND: Ulceration of the feet, which can result in loss of limbs and even death, is one of the major health problems for people with diabetes mellitus. OBJECTIVES: To assess the effects of patient education on the prevention of foot ulcers in patients with diabetes mellitus. SEARCH METHODS: We searched The Cochrane Wounds Group Specialised Register (searched 03 September 2014); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 8). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) that evaluated educational programmes for preventing foot ulcers in people with diabetes mellitus. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook data extraction and assessment of risk of bias. Primary end points were foot ulceration or ulcer recurrence and amputation. MAIN RESULTS: Of the 12 RCTs included, the effect of patient education on primary end points was reported in only five. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. One of the RCTs showed reduced incidence of foot ulceration (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.14 to 0.66) and amputation (RR 0.33, 95% CI 0.15 to 0.76) during one-year follow-up of diabetes patients at high risk of foot ulceration after a one-hour group education session. However, one similar study, with lower risk of bias, did not confirm this finding (RR amputation 0.98, 95% CI 0.41 to 2.34; RR ulceration 1.00, 95% CI 0.70 to 1.44). Three other studies, also did not demonstrate any effect of education on the primary end points, but were most likely underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self-reported self-care behaviour in the short term in seven of nine RCTs. Callus, nail problems and fungal infections improved in only one of five RCTs. Only one of the included RCTs was at low risk of bias. AUTHORS' CONCLUSIONS: In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. Yet, based on the only two sufficiently powered studies reporting the effect of patient education on primary end points, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence.

High-dose statin therapy in patients with stable coronary artery disease: treating the right patients based on individualized prediction of treatment effect.

BACKGROUND: Clinicians need to identify coronary artery disease patients for whom the benefits of high-dose versus usual-dose statin therapy outweigh potential harm. We therefore aimed to develop and validate a model for prediction of the incremental treatment effect of high-dose statins for individual patients in terms of reduction of 5-year absolute risk for myocardial infarction, stroke, coronary death, or cardiac resuscitation. METHODS AND RESULTS: Based on data from the Treating to New Targets trial (TNT; n=10 001), a Cox proportional hazards model was developed comprising 13 easy-to-measure clinical predictors: age, sex, smoking, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, history of myocardial infarction, coronary artery bypass grafting, congestive heart failure or abdominal aortic aneurysm, glomerular filtration rate, and treatment status (ie, atorvastatin 80 mg or 10 mg). External validation in the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial (IDEAL; n=8888) confirmed adequate goodness-of-fit and calibration, but moderate discrimination (C-statistic, 0.63; 95% confidence interval, 0.62-0.65). Still, among participants of both trials combined, the model identified a group of 11.7% whose predicted 5-year number needed to treat was ≤25 and a group of 41.9% whose predicted needed to treat was ≥50. A decision curve shows that making treatment decisions on the basis of predictions using our model may improve net benefit. CONCLUSIONS: Estimation of the incremental treatment effect of high-dose versus usual-dose statin therapy in individual coronary artery disease patients enables selection of high-risk patients that benefit most from more aggressive therapy. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00327691 and NCT00159835.

Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.

OBJECTIVES: To enable risk stratification of patients with various types of arterial disease by the development and validation of models for prediction of recurrent vascular event risk based on vascular risk factors, imaging or both. DESIGN: Prospective cohort study. SETTING: University Medical Centre. PATIENTS: 5788 patients referred with various clinical manifestations of arterial disease between January 1996 and February 2010. MAIN OUTCOME MEASURES: 788 recurrent vascular events (ie, myocardial infarction, stroke or vascular death) that were observed during 4.7 (IQR 2.3 to 7.7) years' follow-up. RESULTS: Three Cox proportional hazards models for prediction of 10-year recurrent vascular event risk were developed based on age and sex in addition to clinical parameters (model A), carotid ultrasound findings (model B) or both (model C). Clinical parameters were medical history, current smoking, systolic blood pressure and laboratory biomarkers. In a separate part of the dataset, the concordance statistic of model A was 0.68 (95% CI 0.64 to 0.71), compared to 0.64 (0.61 to 0.68) for model B and 0.68 (0.65 to 0.72) for model C. Goodness-of-fit and calibration of model A were adequate, also in separate subgroups of patients having coronary, cerebrovascular, peripheral artery or aneurysmal disease. Model A predicted < 20% risk in 59% of patients, 20-30% risk in 19% and > 30% risk in 23%. CONCLUSIONS: Patients at high risk for recurrent vascular events can be identified based on readily available clinical characteristics.

The daily 10 kcal expenditure deficit: a before-and-after study on low-cost interventions in the work environment.

OBJECTIVES: To evaluate whether four types of low-cost interventions in the working environment can promote the small everyday lifestyle adaptations that can halt the epidemics of obesity and hypertension when maintained long term. DESIGN: A single-blind uninterrupted time-series intervention study consisting of four study periods: run-in (2 weeks), baseline (2 weeks), intervention (2 weeks), and after intervention 2 weeks). SETTING: University Medical Centre with over 11 000 employees, over 1000 hospital beds and over 2000 customers visiting the hospital restaurant each day. PARTICIPANTS: Hospital staff and visitors. INTERVENTIONS: (1) Point-of-decision prompts on hospital elevator doors promoting stair use. (2) Point-of-purchase prompts in the hospital restaurant promoting reduced-salt soup. (3) Point-of-purchase prompts in the hospital restaurant promoting lean croissants. (4) Reversal of the accessibility and availability of diet margarine and butter in the hospital restaurant. MAIN OUTCOME MEASURES: (1) Number of passages through 15 different parts of the hospital staircases. (2) Number and ratio of normal-salt and reduced-salt soup purchased. (3) Number and ratio of butter croissants and lean croissants purchased. (4) Number and ratio of diet margarine and butter purchased. RESULTS: Elevator signs increased the mean 24-h number of stair passages per measurement site (baseline: 992 ± 479 on week days and 208 ± 116 on weekend days) by 11.2% (95% CI 8.7% to 13.7%). This effect was maintained at least 2 weeks after the point-of-decision prompts were removed. Point-of-purchase prompts promoting low-salt soup and lean croissants did not result in altered purchase behaviour. The ratio between the purchase of margarine and butter was changed sevenfold (p<0.01) by reversing the positions of these products in the hospital restaurant. CONCLUSIONS: Healthy lifestyle adaptations in the working environment can be effectively promoted by making healthy choices easier than unhealthy ones. Educational prompts at points-of-decision moderately increase stair climbing, but do not affect healthy food choices. PROTOCOL REGISTRATION: Clinicaltrials.gov identifier number: NCT01574040.

Differential effects of renin-angiotensin-aldosterone system inhibition, sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension: a double-blind, placebo-controlled cross-over trial.

OBJECTIVES: The objective of this study is to determine the effects of renin-angiotensin-aldosterone system inhibition, sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension. METHODS: A randomized, four-way, double-blind, crossover study in 31 adults with previously untreated obesity-related hypertension, in which the effects of 8 weeks' inhibition of the renin-angiotensin-aldosterone system (using aliskiren 300 mg), sympathoinhibition (using moxonidine 0.4 mg), diuretic therapy (using hydrochlorothiazide 25 mg) or placebo on flow-mediated dilation and 24-h blood pressure were compared. RESULTS: The median flow-mediated dilation during placebo was 4.0% [interquartile range (IQR) 2.9-5.5%] and was increased by aliskiren [0.81%, 95% confidence interval (CI) 0.02-1.79], but not by moxonidine (0.20%, 95% CI -0.46 to 1.03) or hydrochlorothiazide (0.39%, 95%CI -0.31%-1.26%). Similarly, compared with placebo, mean 24-h blood pressure was most reduced by aliskiren (-9.8/-6.3 mmHg) and to a lesser degree by hydrochlorothiazide (-5.9/-2.6 mmHg). Moxonidine did not significantly affect blood pressure despite reduction of muscle sympathetic nerve activity. Insulin sensitivity deteriorated during hydrochlorothiazide treatment and was unaffected by aliskiren or moxonidine. Unlike aliskiren and moxonidine, hydrochlorothiazide reduced urinary 8-iso-prostaglandin F2α-VI, a marker of oxidative stress. Vascular stiffness, systemic inflammation, leptin, adiponectin and other oxidative stress markers (plasma malondialdehyde, myeloperoxidase activity and urinary 8-hydroxydeoxyguanosine) were unaffected by treatment. CONCLUSION: Renin inhibition, but not sympathoinhibition or diuretic therapy, improves endothelial function and results in larger reductions of 24-h, office, and central blood pressure in obesity-related hypertension. This adds weight to the hypothesis that inhibition of the renin-angiotensin-aldosterone system is an effective first step in the treatment of obesity-related hypertension.

Relation between adiposity and hypertension persists after onset of clinically manifest arterial disease.

OBJECTIVES: To quantify the relation between adiposity and blood pressure (BP) level in patients with symptomatic vascular disease and, thereby, assess whether the obesity paradox can be explained by a causal mechanism involving BP. METHODS: BP and markers of adiposity (i.e. weight, body mass index, waist circumference, waist-to-hip ratio, subcutaneous adipose tissue, and visceral adipose tissue) were recorded in 4556 men and women with symptomatic vascular disease enrolled in the Secondary Manifestations of Arterial Disease Study. Additionally, 185 patients underwent repeated measurements after 3.7 years follow-up. RESULTS: Each 5 kg/m(2) body mass index was associated with +3.8 mmHg (95% confidence interval (CI) 3.0-4.6) SBP difference and +2.3 mmHg (95% CI 1.9-2.8 mmHg) DBP difference in both men and women. Measures of centralized adiposity compared with BMI were equally related with BP. In contrast, subcutaneous adipose tissue was only weakly related with DBP and not related with SBP and pulse pressure. Various methods of adjustment for BP-lowering medication use led to consistent results. Furthermore, 5 kg/m(2) body mass index change during follow-up was associated with +8.1/5.1 mmHg BP change. CONCLUSION: The relation between general and abdominal adiposity and hypertension persists after onset of symptomatic arterial disease both in men and women. This shows that the obesity paradox cannot be explained by a causal mechanism involving BP and, therefore, supports weight control for reducing BP in secondary prevention of cardiovascular events.

Patient education for preventing diabetic foot ulceration.

BACKGROUND: Ulceration of the feet, which can result in loss of limbs and even death, is one of the major health problems for people with diabetes mellitus. OBJECTIVES: To assess the effects of patient education on the prevention of foot ulcers in patients with diabetes mellitus. SEARCH METHODS: Eligible studies were identified by searching The Cochrane Wounds Group Specialised Register (searched 1 August 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7); Ovid MEDLINE (2009 to July Week 3 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, July 31, 2012); Ovid EMBASE (2009 to 2012 Week 30); and EBSCO CINAHL (2009 to 26 July 2012). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) that evaluated educational programmes for preventing foot ulcers in people with diabetes mellitus. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook data extraction and assessment of risk of bias. Primary end points were foot ulceration or ulcer recurrence and amputation. MAIN RESULTS: Of the 12 RCTs included, the effect of patient education on primary end points was reported in only five. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. One of the RCTs showed reduced incidence of foot ulceration (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.14 to 0.66) and amputation (RR 0.33, 95% CI 0.15 to 0.76) during one-year follow-up of diabetes patients at high risk of foot ulceration after a one-hour group education session. However, one similar study, with lower risk of bias, did not confirm this finding (RR amputation 0.98, 95% CI 0.41 to 2.34; RR ulceration 1.00, 95% CI 0.70 to 1.44). Three other studies, also did not demonstrate any effect of education on the primary end points, but were most likely underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self-reported self-care behaviour in the short term in seven of nine RCTs. Callus, nail problems and fungal infections improved in only one of five RCTs. Only one of the included RCTs was at low risk of bias. AUTHORS' CONCLUSIONS: In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. Yet, based on the only two sufficiently powered studies reporting the effect of patient education on primary end points, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence.

Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors.

OBJECTIVE: Endocrine diseases that can be part of the rare inheritable syndrome multiple endocrine neoplasia type 1 (MEN1) commonly occur in the general population. Patients at risk for MEN1, and consequently their families, must be identified to prevent morbidity through periodic screening for the detection and treatment of manifestations in an early stage. The aim of the study was to develop a model for predicting MEN1 in individual patients with sporadically occurring endocrine tumors. DESIGN: Cross-sectional study. METHODS: In a nationwide study in The Netherlands, patients with sporadically occurring endocrine tumors in whom the referring physician suspected the MEN1 syndrome were identified between 1998 and 2011 (n=365). Logistic regression analysis with internal validation using bootstrapping and external validation with a cohort from Sweden was used. RESULTS: A MEN1 mutation was found in 15.9% of 365 patients. Recurrent primary hyperparathyroidism (pHPT; odds ratio (OR) 162.40); nonrecurrent pHPT (OR 25.78); pancreatic neuroendocrine tumors (pNETs) and duodenal NETs (OR 17.94); pituitary tumor (OR 4.71); NET of stomach, thymus, or bronchus (OR 25.84); positive family history of NET (OR 4.53); and age (OR 0.96) predicted MEN1. The c-statistic of the prediction model was 0.86 (95% confidence interval (95% CI) 0.81-0.90) in the derivation cohort and 0.77 (95% CI 0.66-0.88) in the validation cohort. CONCLUSION: With the prediction model, the risk of MEN1 can be calculated in patients suspected for MEN1 with sporadically occurring endocrine tumors.

Patient education for preventing diabetic foot ulceration.

Treatment of diabetic foot ulceration is very challenging, costly and often needs to be of long duration. This leads to substantial economic burden. Population-based research suggests that a meaningful reduction of the incidence of amputations caused by diabetes mellitus has already been achieved since the St. Vincent resolution in 1989. Still, it cannot be inferred from these studies that the current preventive efforts are (cost-)effective because reduction of amputation incidence can also be the result of improvements in ulcer treatment. Nevertheless, education of people with diabetes is widely advocated and implemented in standard practice. Despite the fact that preventive interventions are often combined in daily practice, there is little scientific evidence demonstrating the effect of those efforts. In systematically reviewing the evidence, there is insufficient evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence. To date, high quality evidence that more complex interventions including patient education can prevent diabetic foot ulceration is not available either. This, however, should be interpreted as lack of evidence rather than evidence of no effect. Future directions for research and practice may be to concentrate preventive effort on those patients who appear to be at highest risk of foot ulceration after careful screening and selection.

Relation between blood pressure and vascular events and mortality in patients with manifest vascular disease: J-curve revisited.

Recent studies have challenged the notion that "lower is better" for blood pressure in relation to vascular events and mortality in patients with vascular disease, whereas practice guidelines currently recommend to lower blood pressure to <130/80 mm Hg. We reassessed this J-curved relationship between blood pressure and cardiovascular events and all-cause mortality in patients with various manifestations of vascular disease. For this purpose, 5788 patients with symptomatic vascular disease enrolled in the Secondary Manifestations of Arterial Disease Study were followed-up for the occurrence of new vascular events (ie, myocardial infarction, stroke, or vascular death) and all-cause mortality. During a median of 5.0 years (interquartile range: 2.6-8.1 years), 788 patients experienced a new vascular event, and 779 died. Overall, the covariate-adjusted relationship between mean baseline systolic, diastolic, or pulse pressure and the occurrence of vascular events followed a J-curve with increased event rates above and below the nadir blood pressure of 143/82 mm Hg. A similar nonlinear relationship was found for diastolic pressure and all-cause mortality. Elevated blood pressure was not associated with increased morbidity and mortality in patients with recently diagnosed coronary artery disease, ≥65 years, and having >60 mm Hg pulse pressure. Importantly, especially in these subgroups, low blood pressure could also be a symptom rather than a cause of disease. Blood pressure level below and above 143/82 mm Hg is, thus, an independent risk factor for recurrent events in patients with manifest vascular disease. Uncertainty of whether this association is causal provides a strong rationale for trials evaluating blood pressure treatment targets.

Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects.

AIMS To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics. METHODS AND RESULTS Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50. CONCLUSION Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.

Estimating treatment effects for individual patients based on the results of randomised clinical trials.

OBJECTIVES: To predict treatment effects for individual patients based on data from randomised trials, taking rosuvastatin treatment in the primary prevention of cardiovascular disease as an example, and to evaluate the net benefit of making treatment decisions for individual patients based on a predicted absolute treatment effect. SETTING: As an example, data were used from the Justification for the Use of Statins in Prevention (JUPITER) trial, a randomised controlled trial evaluating the effect of rosuvastatin 20 mg daily versus placebo on the occurrence of cardiovascular events (myocardial infarction, stroke, arterial revascularisation, admission to hospital for unstable angina, or death from cardiovascular causes). Population 17,802 healthy men and women who had low density lipoprotein cholesterol levels of less than 3.4 mmol/L and high sensitivity C reactive protein levels of 2.0 mg/L or more. METHODS: Data from the Justification for the Use of Statins in Prevention trial were used to predict rosuvastatin treatment effect for individual patients based on existing risk scores (Framingham and Reynolds) and on a newly developed prediction model. We compared the net benefit of prediction based rosuvastatin treatment (selective treatment of patients whose predicted treatment effect exceeds a decision threshold) with the net benefit of treating either everyone or no one. RESULTS: The median predicted 10 year absolute risk reduction for cardiovascular events was 4.4% (interquartile range 2.6-7.0%) based on the Framingham risk score, 4.2% (2.5-7.1%) based on the Reynolds score, and 3.9% (2.5-6.1%) based on the newly developed model (optimal fit model). Prediction based treatment was associated with more net benefit than treating everyone or no one, provided that the decision threshold was between 2% and 7%, and thus that the number willing to treat (NWT) to prevent one cardiovascular event over 10 years was between 15 and 50. CONCLUSIONS: Data from randomised trials can be used to predict treatment effect in terms of absolute risk reduction for individual patients, based on a newly developed model or, if available, existing risk scores. The value of such prediction of treatment effect for medical decision making is conditional on the NWT to prevent one outcome event. Trial registration number Clinicaltrials.gov NCT00239681.

Patient education for preventing diabetic foot ulceration.

BACKGROUND: Ulceration of the feet, which can result in loss of limbs and even death, is one of the major health problems for people with diabetes mellitus. OBJECTIVES: To assess the effects of patient education on the prevention of foot ulcers in patients with diabetes mellitus. SEARCH STRATEGY: Eligible studies were identified by searching the Cochrane Wounds Group Specialised Register (22 December 2009), the Cochrane Central Register of Controlled Trials (Cochrane Library 2009 Issue 4 ), Ovid MEDLINE (1950 to November Week 3 2009), Ovid MEDLINE In-Process & Other Non-Indexed Citations (Searched 22/12/09), Ovid EMBASE (1980 to 2009 Week 51) and EBSCO CINAHL (1982 to December 22 2009). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) which evaluated educational programmes for preventing foot ulcers in people with diabetes mellitus. There was no restriction on language of the publications. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook data extraction and assessment of risk of bias. Primary end-points were foot ulceration or ulcer recurrence and amputation. MAIN RESULTS: Eleven RCTs were included. Three studies described the effect of foot care education as part of general diabetes education compared with usual care. Two studies examined the effect of foot care education tailored to educational needs compared with no intervention. Finally, six studies described the effect of intensive compared with brief educational interventions. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. Four RCTs assessed the effect of patient education on primary end-points: foot ulceration and amputations. One of these studies reported a statistically significant benefit of one hour group education after one year of follow-up in people with diabetes who were at high risk for foot ulceration; RR amputation 0.33 (95% CI 0.15 to 0.76); RR ulceration 0.31 (95% CI 0.14 to 0.66), however this study was at high risk of bias and may have overestimated the effect due to a unit of analysis error. One similar, but methodologically superior study did not confirm this finding; RR amputation 0.98 (95% CI 0.41 to 2.34); RR ulceration 1.00 (95% CI 0.70 to 1.44). The other two studies did not detect any effect of education on ulcer incidence or amputation but were underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self reported self care behaviour in the short term in seven of nine RCTs. The effects on callus, nail problems and fungal infections were described in five of the included studies, of which only two reported temporary improvements after an educational intervention.Only one of the included RCTs was considered to be at low risk of bias. AUTHORS' CONCLUSIONS: Most of the RCTs included in this review are at high or unclear risk of bias. In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. This, however, must be viewed with caution. The ultimate goal of educational interventions is preventing foot ulceration and amputation but only four RCTs reported these outcomes and only two reported sufficient data to examine this. Based on these two studies, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence.Future research should focus on evaluating the effect of more comprehensive and/or intensive prevention strategies which may also include patient education (complex interventions).

Complex interventions for preventing diabetic foot ulceration.

BACKGROUND: Ulceration of the feet, which can lead to the amputation of feet and legs, is a major problem for people with diabetes mellitus, and can cause substantial economic burden. Single preventive strategies have not been shown to reduce the incidence of foot ulceration to a significant extent. Therefore, in clinical practice, preventive interventions directed at patients, health care providers and/or the structure of health care are often combined (complex interventions). OBJECTIVES: To assess the effectiveness of complex interventions on the prevention of foot ulcers in people with diabetes mellitus compared with single interventions, usual care or alternative complex interventions. A complex intervention is defined as an integrated care approach, combining two or more prevention strategies on at least two different levels of care: the patient, the healthcare provider and/or the structure of healthcare. SEARCH STRATEGY: Eligible studies were identified by searching the Cochrane Wounds Group Specialised Register (28/05/09), the Cochrane Central Register of Controlled Trials (CENTRAL, 28 May 2009), Ovid MEDLINE (1950 to May Week 3 2009), Ovid EMBASE (1980 to 2009 Week 21) and EBSCO CINAHL (1982 to May Week 4 2009). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) which compared the effectiveness of combinations of preventive strategies, not solely patient education, for the prevention of foot ulcers in people with diabetes mellitus, with single interventions, usual care or alternative complex interventions. DATA COLLECTION AND ANALYSIS: Two review authors were assigned to independently select studies, to extract study data and to assess risk of bias of included studies, using predefined criteria. MAIN RESULTS: Only five RCTs met the criteria for inclusion. The study characteristics differed substantially in terms of health care settings, the nature of the interventions studied and outcome measures reported. In three studies that compared the effect of an education centred complex intervention with usual care or written instructions only, little evidence of benefit was found. Two studies compared the effect of more intensive and comprehensive complex interventions with usual care. One of these reported improvement of patients' self care behaviour. In the other study a significant and cost-effective reduction of lower extremity amputations (RR 0.30 (95% CI 0.13 to 0.71)) was achieved. All five included RCTs were at high risk of bias; with hardly any of the predefined quality assessment criteria met. AUTHORS' CONCLUSIONS: There is no high quality research evidence evaluating complex interventions for preventing diabetic foot ulceration and insufficient evidence of benefit.