It is well known that hypertension control is non-satisfactory, but it is not clear how many hypertensive patients can be controlled in real life. We addressed this question implementing a simple, multifaceted improvement strategy in family practice.Eighteen General Practitioner (GPs) agreed upon a simple improvement strategy including: 1) the use of occasional direct/indirect contacts (prescription refilling) to decrease missing blood pressure (BP) recording, and to increase therapeutic adherence, 2) the use of home BP measurements in non-controlled patients, 3) the addition of a new drug in non-controlled, but adequately adherent patients. Results were assessed after one year by automatic data extraction from the clinical records of all hypertensive subjects.The patients with a diagnosis of hypertension increased from 6.309  to 6.717 : prevalence 25.3% to 27.0%. The BP recording increased: 4,305 patients (68.2%) vs 4,948 patients (78.4%) , as well as the BP control: 3,203  vs 4,043  .Almost 82% of hypertensive subjects who contact their doctors can be easily controlled. Most non-controlled patients simply don’t see their GPs; in almost all the remaining non-controlled patients GPs fail to increase drug therapy. A further improvement is therefore possible. Hypertension is a leading modifiable risk factor for cardiovascular disease. Worldwide, 7.6 million premature deaths  and 92 million DALYs , about 54% of stroke and 47% of ischemic heart disease were attributable to high blood pressure [The reasons for low control rate in surveys can be divided into insufficient blood pressure measurement and recording, and insufficient treatment (prescription and adherence).The great majority of hypertensive patients are cared for in primary care. The analysis of every-day practice shows a problem which cannot be identified by the observation of a randomly selected and carefully evaluated sample of a hypertensive population: many subjects diagnosed with high blood pressure have no up-to-date blood pressure (BP) values in their clinical records. A recent survey in Italian primary care showed that, during the last year, 16% of diagnosed hypertensive subjects didn’t visit their GPs: furthermore, of the patients who contacted their GP 16% had no recorded BP value  over 90%Other well-known obstacles to getting patients to BP target are drug under-prescription (therapeutic inertia) and poor therapeutic continuity/adherence . In concThe scientific literature is rich in trials aiming to improve drug prescription, therapeutic adherence, patient involvement, and, finally, BP control. Unfortunately, a definite model is still lacking, and only general suggestions are possible, at least according to Cochrane Collaboration’s conclusion, in which he states that: “family practices and community-based clinics need to have an organized system of regular follow-up and review of their hypertensive patients…. Self-monitoring and appointment reminders may be useful adjuncts to the above strategies to improve blood pressure control, but require further evaluation” . It is cIn Italy every resident is registered with a GP who cares for his/her patients at no charge ; there is no limitation to access to office visits, and anti-hypertensive drugs are free of charge, thus eliminating two possible causes of under-treatment. Eighteen GPs, all members of the Italian College of General Practitioners (working in different towns), and particularly interested in hypertension management, decided to maximize their effort to improve BP control. They agreed upon a simple strategy, compatible with primary care organization in Italy, including the following steps: 1) appropriate technique for BP measurement, 2) systematic use of direct and indirect contacts to remind patients to regularly check BP, and to adhere to drug prescription, and 3) an increase in drug-therapy in non-controlled, adherent patients. The improvement strategy, aiming to implement better blood pressure measurement, empowerment of patients, and higher therapeutic adherence, was autonomously decided upon by the authors themselves together with the other GPs who participated in the improvement effort. This strategy was agreed upon by all the participating GPs. The treatment the patients received was consistent with good clinical practice. The clinical data were recorded according to the current standard of care, and were rendered anonymous by the GP who cared for the hypertensive patients. For these reasons, consent from patients or approval by an ethics committee was not required before the implementation of the improvement strategy, according to Italian law .All the GPs decided to systematically identify the uncontrolled patients who needed home monitoring (or 24 hour monitoring) according to the ESH . The parA patient was considered controlled when the office BP was < 140/90 mmHg,and/or the mean home BP was < 135/85 mmHg, and/or the mean 24 hour BP was < 126/80 mmHg .th 2011. The following items were extracted over the period 2009/06/01-2011/06/30: CV diseases, prescribed drugs, recorded BP and methods for measurements, as well as pertinent blood tests. Data recorded from 2009/06/01 to 2010/05/31 were used to analyse baseline practice. The last available BP (baseline and observation period) was used to classify the patient as “controlled” or “not controlled”.The GPs began to implement this improvement strategy in June 2010; the data rendered anonymous for the final evaluation were automatically extracted from the GPs’ database on June 30Therapeutic adherence was calculated considering the single pill as the “prescribed daily dose”; only the anti-hypertensive drugs continuously prescribed from 2009/01/01 to 2011/06/30 were used to compare adherence at baseline and at the end of the observation period, and for every single patient only the drug with the best baseline adherence was considered for comparison.Continuous variables were reported as mean and standard deviation, whereas categorical variables were expressed as numbers and percentages; paired t-tests and McNemar test were respectively used for comparisons. Two-tailed p-values less than 0.05 were considered significant. All analyses were performed using SPSS for Windows, version 18.0.The participating GPs cared for 24,918 subjects aged ≥ 15; 5 GPs worked in cities, 7 worked in towns, and 6 in small towns or semirural areas; 7 worked in Northern, 8 in Central, and 3 in Southern Italy. Their baseline performances differed widely  was ambulatory or home-based in 135 (2.1%) and 735 (11.7%) subjects. Among the patients “non-controlled” with office measurement, none had at least one previous “controlled” value with home or ambulatory monitoring.The mean number of anti-hypertensive drug increased from 1.17  at baseline to 1.18  at the end of the observation period: + 0.01 ± 0.66 (p < 0.001); further details on drug prescription are reported in Table The mean number of days in therapy permitted by the recorded prescribed drugs increased from 229 to 236: + 7 ± 83 (p < 0.001); further details on adherence are reported in Tables The main achievement of our improvement strategy regarded home-monitoring, which was extensively used, according to the recent guidelines ; this isThe improvement of BP control is mainly due to a better blood pressure measurement and only to a lesser extent perhaps to a real blood pressure reduction based on improved adherence to antihypertensive treatment.In particular, the relevant increase in controlled patients seems to come more from the reduction of “white coat BP rise” due to appropriate BP measurement methods than from a better use of drugs, although the increased adherence may have played a role. “White coat effect on blood pressure”,’ may account for a noticeable fraction (one fourth or more) of individuals in whom hypertension is diagnosed . The perOur simple approach leads to a control rate of almost 82% in patients who contacted their GPs, and of 64% in the whole hypertensive population. These results compare favorably with those reported by a recent study in British General Practice, where patients randomized to intensive management were controlled in 63% of cases. Our achievement is even more remarkable considering that the protocol of the British study excluded the most-difficult-to-control subjects. It is probable that the use of office BP measurement as a standard to evaluate BP control can explain at least part of this difference .Despite the initial agreement among the participating GPs, the increase in drug use is very small, and the association of different drugs remains sub-optimal, as well as lower than that used in the UK, according to the nhs.uk/statistics-and-data-collections , which rMost of our non-controlled patients use one drug, thus the most important way to further improve BP control could be to move to a two-drug therapy when one is not enough. Therapeutic inertia proves to be an obstacle that is hard to overcome, but improvement in this field could lead to an even higher BP control rate. The most useful strategy, at least in order to avoid inappropriate single-drug prescription, could be to skip the problem and to start with a solution of two-drug association when the initial value of BP shows that a single drug will not be enough to reach full control, as suggested by the European guidelines .Our study presents many limits, directly related to having been conceived as a spontaneous effort to improve the personal clinical practice, and not as a formal study. For this reason no pre-specified control on the quality, and degree of practice modification was possible. Another important limit is the absence of a control group. On the other hand, comparison of relevant management changes in the same population before and after the introduction of practice modification is common in medical literature; a well-known example being the studies on the effectiveness of the “pay for performaces” contracts . DespiteFinally, the problem of patients without BP recording and/or lack of contact deserve a comment. The number of patients with recorded BP increased to 78.4%. This percentage is lower than that reported by British GPs after their “pay per performances” contract, but any comparison is impaired by the very low hypertension prevalence  according to their recorded diagnoses ; such a Extensive use of home BP monitoring and systematic use of direct and indirect contacts to improve patients’ compliance increase the BP control rate up to over 80% in unselected hypertensive subjects who contact their doctors. Despite explicit commitment on the part of the GPs to overcome therapeutic inertia, the use of multiple drugs didn’t increase, thus impairing an even higher BP control rate. Despite the GPs’ efforts, more than 20% of hypertensive patients remain unwilling/unable to contact their physicians; new strategies to tackle this problem are needed.The authors declare that they have no competing interests.AF prepared the improvement strategy and wrote the paper; DS and SB performed the statistical analysis, LD contributed to writing and reviewing the paper, GN, IP, and ADG contributed to preparing the improvement strategy, supporting the participating GPs , and to reviewing the paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/14/192/prepub


Systolic blood pressure variability is an independent risk factor for mortality and cardiovascular events. Standard measures of blood pressure predict outcome poorly in haemodialysis patients. We investigated whether systolic blood pressure variability was associated with mortality in incident haemodialysis patients. We performed a longitudinal observational study of patients commencing haemodialysis between 2005 and 2011 in East Anglia, UK, excluding patients with cardiovascular events within 6 months of starting haemodialysis. The main exposure was variability independent of the mean (VIM) of systolic blood pressure from short-gap, pre-dialysis blood pressure readings between 3 and 6 months after commencing haemodialysis, and the outcome was all-cause mortality. Of 203 patients, 37 (18.2%) patients died during a mean follow-up of 2.0 (SD 1.3) years. The age and sex-adjusted hazard ratio (HR) for mortality was 1.09  1.02–1.17) for a one-unit increase of VIM. This was not altered by adjustment for diabetes, prior cardiovascular disease and mean systolic blood pressure . Patients with VIM of systolic blood pressure above the median were 2.4 (95% CI 1.17–4.74) times more likely to die during follow-up than those below the median. Results were similar for all measures of blood pressure variability and further adjustment for type of dialysis access, use of antihypertensives and absolute or variability of fluid intake did not alter these findings. Diastolic blood pressure variability showed no association with all cause mortality. Our study shows that variability of systolic blood pressure is a strong and independent predictor of all-cause mortality in incident haemodialysis patients. Further research is needed to understand the mechanism as this may form a therapeutic target or focus for management. Mortality is high among patients undergoing haemodialysis treatment for end-stage renal disease (ESRD), and cardiovascular disease is the main cause of death Blood pressure (BP) variability is more closely associated with adverse outcomes in patients with or at risk of vascular disease than ‘usual’ BP BP variability can be quantified over both the short term, using 24-hour ambulatory BP measurements, and long-term using visit-to-visit BP readings st 2005 and December 12th 2010. Patients were from Addenbrookes Hospital and four satellite units in East Anglia, England. Each underwent haemodialysis three times a week and each dialysis session was at the same time of day and lasted for 3–4 hours.We performed a longitudinal cohort study of patients who commenced maintenance haemodialysis between January 1We included all patients who were aged over 18 years at the start of dialysis, had no history of prior renal replacement therapy including transplantation, and remained on dialysis for more than 180 days with no recovery of kidney function. To avoid reverse causality (where underlying cardiovascular disease causes variable blood pressure), we excluded patients who died or suffered cardiovascular events , myocardial infarction, angina or heart failure) in the first 180 days after starting haemodialysis.th to 6th months after commencing haemodialysis. BP readings from the first 3 months after commencing dialysis were not used because this period is associated with acute illness and frequent adjustments to fluid weight and medications, which may have led to overestimation of BP variability in more unwell patients. We used pre-dialysis BP readings to minimise the effect of change in BP due to fluid removal during haemodialysis. We excluded BP readings taken on the first dialysis session of each week to avoid the possible confounding effects of fluid gains over the extended three-day weekend break. Therefore over the 3-month observation period all patients included in the analysis had almost identical numbers of BP readings included in the measurement of the exposure and these were 2 BP readings per week taken 2 days apart on the same day and same time of day for each individual.BP was measured was measured at the beginning and end of each dialysis session in a seated position by trained dialysis nurses in accordance with routine unit practice and entered immediately into an electronic database. BP was measured using validated oscillometric BP monitor equipped haemodialysis machines (Fresenius 4008S or Nikisso DBB-05), which were maintained as per dialysis unit protocols. For each patient we analysed pre-dialysis BP readings obtained over a consecutive 3-month period, from the 4We measured intra-individual BP variability for both pre-dialysis systolic and diastolic BP using standard deviation, coefficient of variation (standard deviation/mean) and variation independent of the mean (VIM) as previously described x is calculated from fitting a power model:Where And x).. Follow-up was censored if patients received a kidney transplant, switched to peritoneal dialysis or transferred to a different renal unit.The outcome was all-cause mortality during the study period, i.e. from 6 months after the commencement of haemodialysis (at the end of the 3–6 month measurement of the exposure) until the end of follow-up , myocardial infarction, angina, heart failure or peripheral vascular disease) and diabetes were defined as present if recorded in the medical notes. Data on cause of death was not available so it was not possible to analyse cardiovascular mortality separately.The definitions of the exposure  were defined a priori. The demographic characteristics of groups above and below the median of VIM were compared using Mann-Whitney U tests for continuous variables and chi-squared tests for categorical variables.We used Cox proportional hazards models to obtain hazard ratios (HR) and 95% confidence intervals (95% CI) for mortality for people with intraindividual visit-to-visit BP variability as a continuous covariate, and also as a categorical covariate, with BP variability dichotomized at the median. We examined whether the proportional hazards assumption was met using partial residual plots for continuous covariates and log (-log) plots for categorical covariates. Kaplan-Meier plots and log-rank tests were also used to compare survival between the two BP variability groups. We carried out univariate analyses of the effect of intraindividual visit-to-visit blood pressure variability on all-cause mortality. We present results adjusted for age and sex as these were considered important a priori confounders. Further covariates examined in multivariate analysis were based on potential evidence of association with mortality among haemodialysis patients; mean systolic BP (SBP), previous cardiovascular events and diabetes. This dataset was complete for all patients. Data on ethnicity was not available but in this region more than 90% of patients are of Caucasian ethnicity. In further separate analyses we adjusted for type of dialysis access (arteriovenous fistula vs indwelling venous catheter), the use of antihypertensive medication (yes vs no) and the number of antihypertensives taken at three months after start of haemodialysis (start of BP variability measurement), the mean intradialytic weight change and the standard deviation of weight change between dialysis sessions as a marker of variability of fluid intake. For this analysis the standard deviation of interdialytic weight change was log transformed due to skewness. We performed the analysis using SPSS version 21.0 .The study received approval from the Hertfordshire Research Ethics Committee (REC 11/H0311/3). Data was anonymised at source so individual patient consent was not required.We are able to provide anonymized data to researchers upon request.During the study period 219 patients who were eligible for inclusion commenced maintenance haemodialysis in this region with a total follow up time of 409.4 person years. Of these, we did not include in the analysis 7 patients who died or recovered kidney function and 9 who had cardiovascular events within the first 180 days of haemodialysis. Therefore 203 patients were included in the analysis. From a mean of 25 dialysis sessions, the mean number of BP readings used for the analyses was 25 (SD 1.63). Over a mean follow-up period of 2.0 (SD 1.3) years, 37 patients (18.2%) died. Follow-up was censored for 24 (11.8%) patients who underwent kidney transplantation and 5 (2.5%) who switched to peritoneal dialysis. No patients changed renal units during the follow-up period.Baseline characteristics of the study population and patients above and below the median VIM of intraindividual visit-to-visit BP variability are shown in At an individual level, the mean SD of SBP was 17.4 mmHg (SD 5.1 mmHg). After adjusting for age and sex, the HR for total mortality was 1.07  for every mmHg increase in SD of SBP. This was not attenuated after further adjustment for mean SBP, previous cardiovascular events and diabetes  . After aFor the purpose of regression modelling the coefficient of variation (COV) was multiplied by 100 for each patient to allow sensible interpretation of the hazard ratio. The HR for total mortality, adjusted for age and gender, was 1.13  for every 0.01 increase in COV. After adjusting for age, sex, previous cardiovascular disease, diabetes and mean SBP the HR for total mortality was 1.13  for every 0.01 increase in COV . After fAfter adjusting for age and sex, the HR for total mortality was 1.09  for a one-unit increase of VIM. Again, this was not attenuated in the fully adjusted model . Patients with VIM of SBP above the median were 2.4  times more likely to die during follow-up than those below or equal to the median after adjustment for diabetes, prior cardiovascular disease, gender, age and mean SBP .The relationship between VIM of systolic BP and all-cause mortality was not affected by adjustment for the type of dialysis access, the use of antihypertensives, number of antihypertensives used or mean weight change during dialysis sessions –S4. In aInclusion of mean diastolic BP in the fully adjusted models made no important difference to the association between any measure of intraindividual visit-to-visit SBP variability and mortality (data not shown).Measures of intraindividual visit-to-visit diastolic BP variability were not associated with mortality in univariate or multivariate analyses. The age and sex adjusted HR for a one-unit increase in VIM of DBP is 1.02 .Our study shows that intraindividual visit-to-visit variability of systolic BP is associated with all-cause mortality in incident haemodialysis patients, independently of confounders such as age, cardiovascular disease and diabetes. This is seen across measures of BP variability including VIM, which importantly is not correlated with systolic BP. The association between mortality and intraindividual visit-to-visit BP variability is not explained by the type of dialysis access, the use of antihypertensives, absolute fluid intake or variability in fluid intake.This study has a number of strengths. Duration of haemodialysis is associated with aortic stiffening and autonomic neuropathy, and thus previous renal replacement therapy may be associated with increased BP variability in prevalent cohorts However, there are also important limitations. We were not able to adjust for a number of potential cardiovascular risk factors such as smoking, body mass index and cholesterol, as these data were not available. However, among patients with ESRD, the relationship between classic risk factors and risk of adverse events is often weak or reversed and these data may not have affected our findings Mortality in haemodialysis patients is markedly higher than in the general population and cardiovascular disease is the main cause of death The mechanisms that contribute to increased BP variability in patients with ESRD are complex and poorly understood. They include changes in intravascular volume and vasoactive factors , reduced arterial compliance, increased sympathetic innervation and alterations of arterial and cardiopulmonary reflexes In summary, this study shows that in standard care, variability of systolic BP from clinical measurements is a strong and independent predictor of all-cause mortality in incident HD patients, even after adjustments for factors such as age, cardiovascular disease and diabetes. This effect is consistent across different measures of BP variability, including VIM, which avoids the confounding effect of average BP. Further research is needed to understand the mechanism as this may form an important therapeutic target or focus for management in this group.Table S1Results of fully adjusted model for analysis examining the effect of type of dialysis access on relationship between VIM and mortality.(DOCX)Click here for additional data file.Table S2Results of fully adjusted model for analysis examining the effect of antihypertensive use on relationship between VIM and mortality.(DOCX)Click here for additional data file.Table S3Results of fully adjusted model for analysis examining the effect of number of antihypertensives on relationship between VIM and mortality.(DOCX)Click here for additional data file.Table S4Results of fully adjusted model for analysis examining the effect of mean intradialytic weight change (kg) on relationship between VIM and mortality.(DOCX)Click here for additional data file.Table S5Results of fully adjusted model for analysis examining the effect of interdialytic weight variability on relationship between VIM and mortality.(DOCX)Click here for additional data file.


The Control of Allergic Rhinitis and Asthma Test (CARAT10) has been proposed as the first tool to implement the Allergic Rhinitis and its Impact on Asthma initiative guidelines in clinical practice. To serve this purpose, it must have adequate properties to assess the control of an individual over time. This study aimed to prospectively assess the test-retest reliability, responsiveness and longitudinal validity of CARAT10.Adults with asthma and allergic rhinitis were enrolled at 4 outpatient clinics of Portuguese central hospitals. At each of the two visits, 4 to 6 weeks apart, patients filled out CARAT10 and additional questionnaires, followed by a medical evaluation blinded to the questionnaires’ answers.From the 62 patients included, 51 patients completely filled out CARAT10 at both visits. The test-retest reliability, computed as an intra-class correlation coefficient, was 0.82. Regarding responsiveness, a significant change (p = 0.002) of CARAT10 score in clinically unstable patients was observed  and the Guyatt’s responsiveness index was 1.54. As for the longitudinal validity assessment, the correlation coefficients of the changes of CARAT10 scores with those of ACQ5 and symptoms VAS ranged from 0.49 to 0.65, while with the physician assessment of control they ranged from 0.31 to 0.41.CARAT10 has good test-retest reliability, responsiveness and longitudinal validity. It can be used to assess control of allergic rhinitis and asthma, both to compare groups in clinical studies and to evaluate individual patients in clinical practice. Rhinitis and asthma are highly prevalent diseases that are closely associated. A few questionnaires have been developed and validated to assess the control of rhinitis,2 and asWe have previously developed the Control of Allergic Rhinitis and Asthma Test – a 17-item version – employCARAT10 has been proposed as the first tool to implement ARIA guidelines in clinical practice. To servThus, this study aimed to prospectively assess the test-retest reliability, responsiveness and longitudinal validity of CARAT10.This prospective observational study comprised two visits, 4 to 6 weeks apart, and was conducted in the first semester of 2009.Patients were enrolled in 4 allergy outpatient clinics of central hospitals in three Portuguese regions – north (Porto and Gaia), south (Lisbon) and the Azores islands (Ponta Delgada).The study was approved by the Hospital S. João review board (Comissão de Ética para a Saúde) and was given the project nº 120/08. Each patient gave his/her written informed consent.All patients between 18 and 70 years of age, with a medical diagnosis of asthma and allergic rhinitis and at least 6 months of follow-up at the clinic were eligible. Only patients unable to fill the questionnaire were excluded.At each visit, patients were asked to fill CARAT10 and additional tools: the Asthma Control Questionnaire (ACQ5) and threeNO50) were measured according to the 2005 ATS/ERS position statements6,10]cm interval.Patients who were graded between 5.0 and 6.0 in the second visit’s control variation VAS were considered to be clinically stable.We classified the patients’ rhinitis severity according to the ARIA recommendations and the asthma control according to the GINA guidelines. The results from both visits were pooled and were plotted against the scores in CARAT10 and its factors.The CARAT10 internal consistency analysis comprised the assessment of its internal consistency with Cronbach’s α.The test-retest reliability was assessed using intra-class correlation coefficient (ICC) in clinically stable patients between visits.The concurrent validity was studied using Spearman’s correlation coefficients between CARAT10/CARAT factors and 1) control assessment instruments or 2) physician’s assessment.The responsiveness of CARAT10 was evaluated in the group of clinically unstable patients – those with either unstable asthma, unstable rhinitis, or both. We used a paired T-test to assess the within-patient change in the CARAT10 score. Moreover, the Guyatt’s responsiveness index (GRI) was calculated as,18:The longitudinal validity was assessed by Spearman’s correlation coefficients calculated between the variation of the CARAT10 score and the variation of the other measures.a priori predictions for the correlation coefficients were, based on previous studies as follows: (i) 0.6–0.8 with ACQ5; (ii) 0.6–0.8 with the symptoms VAS; (iii) 0.4–0.6 with the physician’s assessment[For hypotheses testing, sessment,10.nd visit. Seven patients in the first visit and 3 in the second incompletely filled out CARAT10  were classified as having clinically stable asthma and rhinitis. The unstable group included 30 patients with both unstable asthma and rhinitis, 9 only with unstable asthma and 5 only with unstable rhinitis.The plots of CARAT10 scores according to the guidelines’ classifications of rhinitis severity and asthma control are shown in Figure a priori predictions and were statistically significant with p < 0.001  control assessment instruments or 2) physician’s assessment met the 1 Table .Concerning responsiveness, we observed a significant within-patient change of CARAT10 scoring in clinically unstable patients . The Guyatt’s responsiveness index was 1.54.a priori predictions, but only one was below 0.4[The correlation coefficients of the measurements variations between visits ranged from 0.49 to 0.65 for ACQ5 and the symptoms VAS, while for the physician assessment of control the coefficients ranged from 0.31 to 0.41. Several correlation coefficients of external measures and CARAT subscores were lower than the elow 0.4. These rReceiver operating characteristic (ROC) curves were plotted, comparing CARAT10’ scores Figure  and subsThe longitudinal assessment of the Control of Allergic Rhinitis and Asthma Test (CARAT10) showed that it has adequate properties to assess individual patients over time.a priori predictions  and researchers are invited to participate. Cross-cultural adaptation of CARAT has started in over 10 different countries[2LEN) network recommendations[The availability of CARAT10 for clinical practice in multiple countries requires cross-cultural validation in other languages. A website to support an adequate process of translation was developed (ountries. It was ndations: forwardIn summary, this study showed that CARAT10 has adequate test-retest reliability, responsiveness and longitudinal validity while confirming its high internal consistency and concurrent validity. Therefore, CARAT10 can be used both in clinical studies and in clinical practice, to compare groups and to evaluate individual patients over time.eNO50: Fraction of exhaled nitric oxide; FEV1: Forced expiratory volume in 1 second; FVC: Forced vital capacity; GA2LEN: Global Allergy and Asthma European Network; GINA: Global Initiative for Asthma; GRI: Guyatt’s responsiveness index; ICC: Intra-class correlation coefficient; PEF: Peak expiratory flow; ROC: Receiver operating characteristic; VAS: Visual analogue scales.ACQ: Asthma control questionnaire; ACT: Asthma Control Test; ARIA: Allergic Rhinitis and its Impact on Asthma; CARAT10: Control of Allergic Rhinitis and Asthma Test; COSMIN: COnsensus-based Standards for the selection of health Measurement Instruments; FJAF declares he has been given honoraria for advisory boards and lectures during meetings from GSK, MSD and Novartis. MMA declares he has been given honoraria for advisory boards and lectures during meetings from GSK, MSD AZ, Faes-pharma and Novartis. JB declares he has been given honoraria for scientific and advisory boards, lectures during meetings and press conferences from StallergÃ¨nes, Actelion, Almirall, AstraZeneca, Chiesi, GSK, Merck, MSD, Novartis, OM Pharma, Sanofi-Aventis, Schering Plough, Teva, Uriach. The remaining authors declare that they have no competing interests.JAF is responsible for the CARAT project, guarantor of the paper and participated in all stages and tasks, LNS participated in the analysis and writing the manuscript draft, ASS participated in data collection and analysis and collaborated in the process of writing the manuscript draft, MMA and ABA participated in study design and reviewed the manuscript; LFA participated in study design, led the data analysis and reviewed the manuscript; JF, MBF, RRA participated in the data collection and reviewed the manuscript and JB provided critical review during the project and reviewed the manuscript. All authors read and approved the final manuscript.Table S1. Frequencies of unanswered questions of CARAT 10 in each visit. Table S2 - Scores and subscores of CARAT 10 in both visits in patients with controlled and uncontrolled rhinitis and asthma. Figures S1 - Study design - data collection and properties evaluation.Click here for file


Hypertension (HTN) is a major worldwide cause of stroke, heart failure, myocardial infarction, and chronic kidney disease. Mechanisms of blood pressure regulation have previously been elucidated from the study of animal models, Mendelian hyper- and hypo-tension in humans, and drug treatment trials. More recently, genome-wide association studies (GWASs) have offered unbiased approaches to identify novel mechanisms contributing to blood pressure control. We and others have reported candidate gene and GWASs that have identified common genetic variants of modest effect on blood pressure that fall in pathways involving natriuretic peptide and nitric oxide signalling -3.NPPA, which encodes the atrial natriuretic peptide (ANP), is associated with higher plasma ANP and lower blood pressure and odds of hypertension [NPR3, encoding the natriuretic peptide clearance receptor, has been associated with blood pressure although it is not associated with plasma ANP or BNP [ENOS, encoding endothelial nitric oxide synthase, is associated with blood pressure and hypertension [GUCY1A3, encoding the alpha subunit of soluble guanylate cyclase, is associated with blood pressure and myocardial infarction risk.Common variant rs5068 in the 3’ UTR of rtension . We havertension ,5. LastlThe natriuretic peptide and nitric oxide systems are important contributors to blood pressure regulation in humans and represent strong targets for pharmacologic intervention to reduce the burden of disease from hypertension.


Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory agents available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. Although these medications are considered safe at low-to-moderate doses, safety concerns with prolonged use of high ICS doses remain; among these concerns is the risk of adrenal suppression (AS). AS is a condition characterized by the inability to produce adequate amounts of the glucocorticoid, cortisol, which is critical during periods of physiological stress. It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy that can persist for up to 1 year after cessation of corticosteroid treatment. If left unnoticed, AS can lead to significant morbidity and even mortality. More than 60 recent cases of AS have been described in the literature and almost all cases have involved children being treated with ≥500 μg/day of fluticasone.The risk for AS can be minimized through increased awareness and early recognition of at-risk patients, regular patient follow-up to ensure that the lowest effective ICS doses are being utilized to control asthma symptoms, and by choosing an ICS medication with minimal adrenal effects. Screening for AS should be considered in any child with symptoms of AS, children using high ICS doses, or those with a history of prolonged oral corticosteroid use. Cases of AS should be managed in consultation with a pediatric endocrinologist whenever possible. In patients with proven AS, stress steroid dosing during times of illness or surgery is needed to simulate the protective endogenous elevations in cortisol levels that occur with physiological stress.This article provides an overview of current literature on AS as well as practical recommendations for the prevention, screening and management of this serious complication of ICS therapy. Asthma is the most common chronic disease among the young, affecting 10% to 15% of Canadian children and adolescents . It is aInhaled corticosteroids (ICSs) are the most effective anti-inflammatory medications available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. The current Canadian standard of care is low-dose ICS monotherapy as first-line maintenance therapy for most children and adults with asthma . RegularIn children of any age, ICS starting doses are similar to those recommended in adults  -- a condition characterized by the inability to produce adequate amounts of cortisol . AS is an under-recognized complication of ICS therapy that, if left unnoticed, can lead to significant morbidity and even mortality -19. The Adrenal insufficiency is a condition in which the adrenal glands are unable to produce adequate amounts of cortisol . It can result from any etiology , and may also be associated with other adrenal hormone deficiencies, such as impaired aldosterone production  for greater than 2 weeks ..54].After systemic absorption, ICSs are metabolized primarily by the liver, and the clearance rate of most ICS medications is typically similar to or somewhat lower than the rate of hepatic blood flow (~90 L/h) Table  53,57].,57.53,57In addition to the PK and PD properties of ICS therapies, it is important to note that clinically significant drug interactions have been noted with a number of ICS medications and potent inhibitors of cytochrome (CYP) 3A4 isozymes, such as ritonavir, ketoconazole, and itraconazole . AS was confirmed with an ACTH stimulation test in the large majority of cases (29) and by other measures of adrenal function in the remaining 4 cases. All cases were treated with high ICS doses (500-2000 μg/day). Despite the fact that the vast majority with AS (91%) were receiving fluticasone, only 16% of all patients were using fluticasone in the UK at the time of this study. All but five children presented with acute hypoglycemia characterized by seizure, decreased levels of consciousness or coma; 1 death was noted. The investigators concluded that the frequency of acute adrenal crisis was greater than expected, particularly in fluticasone-treated children .Apart from exposure to illness or surgery, risk factors for the development of adrenal crisis in children with AS are not well understood. Therefore, increased awareness and early recognition of AS are important to help prevent against this potentially serious consequence of ICS therapy.As highlighted previously, AS often goes unrecognized until physiologic stress precipitates an adrenal crisis. As a result, the frequency of AS in the asthma population is not well documented. Currently, there are no national guidelines for AS screening in children with asthma. Evidence suggests that screening approaches vary widely, and that many children with asthma who are at risk for AS are not screened. Guidelines in the UK state that the use of fluticasone at doses ≥400 μg/day should be accompanied with screening for AS . BrodlieGiven these findings as well as the lack of published guidelines for the prevention, screening and management of AS, the authors have provided the recommendations in this section based on the best available literature and expert opinion.Although ICS therapy represents the mainstay of asthma management, physicians and other healthcare professionals need to be aware of the risk for AS in all asthma patients using ICS therapy, regardless of the dose prescribed. Although most cases have been reported in individuals using high doses of fluticasone, a few cases have also been noted in patients using low ICS doses ,27,91.Recognizing children at risk is imperative, and screening should be considered in any child with symptoms of AS, children using high ICS doses, or those with a history of oral corticosteroid use (see Screening section for more detail). Although poor growth is not always indicative of AS, growth should be monitored every 6 months  and measurements should be plotted on an appropriate growth curve. If, after 6 months, growth velocity appears to be inadequate, the physician should consider all possible etiologies, including AS, as well as referral to an endocrinologist for appropriate testing.Healthcare professionals should educate the parents of children using high ICS doses about the risk of AS and associated symptoms , regardless of the ICS dose utilized  is diagnostic of AS and warrants an urgent referral to a pediatric endocrinologist. If the result is within the laboratory normal range, the child should be screened every 6 months. It is important to remember that the sensitivity of a first morning cortisol measurement is poor and, therefore, a normal value does not rule out the presence of AS. If the child has a normal test result, but symptoms of AS are present, a low-dose ACTH stimulation test should be performed to confirm the diagnosis.2/day) should be considered until the first morning cortisol value normalizes , the endocrinologist on call should be contacted, and the child should be treated with an immediate stress dose of intravenous or intramuscular hydrocortisone (100 mg/m2), followed by 100 mg/m2/day of hydrocortisone, divided into 3 to 4 doses over a 24-hour period [Whenever possible, cases of AS should be managed in consultation with a pediatric endocrinologist. Daily hydrocortisone at a physiologic dose (8-10 mg/mr period . In patir period .Parents and children at risk for AS should be educated about stress steroid dosing and provided with emergency medical contact information in the event of illness. Consideration should be given to providing patients with a Medic-alert bracelet and/or information card detailing their diagnosis, updated medication doses and stress-dosing instructions.In spite of the measurable effects of ICS therapy on the HPA axis, it is important to remember that effective anti-inflammatory therapy is essential for the treatment of asthma, that ICSs are the most effective anti-inflammatory agents available, and that the suppressive effects of ICS therapy on the HPA axis is markedly less than clinically equivalent doses of oral corticosteroids. At low-to-moderate doses, ICS therapy does not present any significant risk for systemic side effects. However, when high doses are used for prolonged periods, serious adverse events, including AS, are possible. The risk for AS can be minimized through increased awareness and early recognition of at-risk patients, regular patient follow-up to ensure the lowest effective ICS doses are utilized, and by choosing an ICS medication with minimal systemic effects. When high-dose ICS therapy is required, important differences in the PK and PD characteristics of the available ICSs warrant consideration in clinical practice. For patients with proven AS, family education and stress steroids during times of illness, injury or surgery are imperative and will help reduce the morbidity associated with this serious complication of ICS therapy.Dr. Alexandra Ahmet has received honoraria for continuing education from Nycomed, MD Briefcase and Peer Review.Allergy, Asthma and Clinical Immunology. He has received consulting fees and honoraria for continuing education from AstraZeneca, GlaxoSmithKline, Graceway Pharmaceuticals, King Pharma, Merck Frosst, Novartis, and Nycomed.Dr. Harold Kim is the past president of the Canadian Network for Respiratory Care and co-chief editor of Dr. Sheldon Spier has received consulting fees and honoraria for continuing medical education from AstraZeneca, Graceway Pharmaceuticals, Merck Frosst and Nycomed.AA contributed to the conception, drafting and writing of the manuscript and to revising it for important intellectual content. HK and SS contributed to the drafting and development of the manuscript and to revising it critically for important intellectual content. All authors read and approved the final manuscript.


In patients with chronic kidney disease studies focusing on platelet function and properties often are non-conclusive whereas only few studies use functional platelet tests. In this study we evaluated a recently developed functional flow cytometry based assay for the analysis of platelet function in chronic kidney disease.Platelet reactivity was measured using flow cytometric analysis. Platelets in whole blood were triggered with different concentrations of agonists . Platelet activation was quantified with staining for P-selectin, measuring the mean fluorescence intensity. Area under the curve and the concentration of half-maximal response were determined.We studied 23 patients with chronic kidney disease  and 19 healthy controls. Expression of P-selectin on the platelet surface measured as mean fluorescence intensity was significantly less in chronic kidney disease patients compared to controls after maximal stimulation with TRAP (9.7 (7.9-10.8) vs. 11.4 (9.2-12.2), P = 0.032), ADP (1.6 (1.2-2.1) vs. 2.6 (1.9-3.5), P = 0.002) and CRP (9.2 (8.5-10.8) vs. 11.5 (9.5-12.9), P = 0.004). Also the area under the curve was significantly different. There was no significant difference in half-maximal response between both groups.In this study we found that patients with chronic kidney disease show reduced platelet reactivity in response of ADP, TRAP and CRP compared to controls. These results contribute to our understanding of the aberrant platelet function observed in patients with chronic kidney disease and emphasize the significance of using functional whole blood platelet activation assays. In chronic kidney disease both bleeding and thrombotic complications are observed. It has been hypothesized that this disturbed balance between pro- and anti-haemostatic factors is involved in the high morbidity and mortality reported in chronic kidney disease-4. EarlyBleeding tendency of patients is characterized by haemorrhagic symptoms and by prolongation of bleeding time. The cauin vitro artifacts as a result of the procedure of platelet isolation, influence of plasma proteins and influence of hematocrit. Therefore we have set up this study with a recently developed, flow cytometer based, functional platelet assay in whole blood, in which these factors are not of influence. With this assay we assessed platelet reactivity in patients with end stage renal disease and cardiorenal syndrome. Both platelet sensitiveness as well as maximal activation of platelets in response to 3 different platelet stimuli was measured, providing an explanation for the disturbed haemostatic balance in patients with renal failure.The balance between thrombosis and bleeds is disturbed in chronic kidney disease. Functional platelet tests are needed to obtain more insight into this balance. However, up to know only a minority of the studies used functional platelet tests and results are non-conclusive,13. ThisPatients were selected from the out-patient clinic of the Meander Medical Center in Amersfoort for this prospective, observational study. Two groups of patients with chronic kidney disease were recruited. The first group consisted of patients with end stage renal disease receiving hemodialysis. In patiIn patients on haemodialysis, the samples were collected before starting the haemodialysis and immediately after the procedure. The first sample was taken from the afferent line directly after inserting the needle in the fistula. The second sample was taken directly after dialysis from the efferent line out of the dialysis machine. In control subjects peripheral venous blood samples were collected from the antecubital vein using 21 gauge needles. A total of 4.5 mL blood was drawn into vacutainer tubes containing 0.5 mL 3.2% sodium-citrate solution as anticoagulant and mixed gently. Blood cell count assays were performed using a haematology analyzer . Hemoglobin, hematocrit, and platelet count were noted.4  and 5 mM KCl (Riedel de Haën), with a pH of 7.4. Fixation was done with a fixation buffer containing 0.2% formaldehyde  in 0.9% NaCL (Sigma-Aldrich). Used fluorochrome-labeled ligands were anti-CD42b fluorescein isothiocyanate (FITC)-labeled mouse antihuman antibody  and anti-CD62P phycoerythrin (PE)-labeled mouse antihuman antibody (BD Pharmingen™). Adenosine diphosphate (ADP)  was used as agonist, as well as thrombin-receptor-associated-peptide (TRAP)  and cross-linked collagen related peptide (CRP) was a generous gift of R. Farndale .For our samples we used HEPES-buffered saline (HBS) containing 10 mM HEPES , 150 mM NaCl , 1 mM MgSOAssays were performed as described before. In shorGraphPad software version 4.0 for Windows  was used to draw graphs and to calculate EC50. EC50 is defined as the concentration of the agonist needed to achieve an effect on the platelets halfway between the maximum and minimum. Area under the curve (AUC) was calculated in SPSS by adding up the outcome minus basal activation outcome of all concentrations points. The data were analyzed by logistic regression for scaled data. For comparisons of nominal variables a Chi-square cross tabulation with a Fisher’s Exact test was used. Statistical analyses were undertaken using SPSS software version 15.0 . A P-value of < 0.05 was considered as statistically significant. Values are given as median with interquartile range (IQR) if not noted otherwise.Twenty-three patients with chronic kidney disease and 19 healthy controls were included. In the chronic kidney disease group, we included 9 patients with cardio renal syndrome and 14 patients with end stage renal failure on hemodialysis . Clinical and laboratory characteristics are listed in Tablep < 0.001; TRAP and CRP 0.538 with p < 0.001; ADP and CRP 0.475 with p = 0.001). TableExpression of P-selectin on the platelet surface measured as MFI was significantly lower in chronic kidney disease patients compared to controls after maximal stimulation with TRAP (9.7 7.9-10.8) vs. 11.4 9.2-12.2), P = 0.032), ADP (1.6 (1.2-2.1) vs. 2.6 (1.9-3.5), P = 0.002) and CRP (9.2 (8.5-10.8) vs. 11.5 (9.5-12.9), P = 0.004).  vs. 47.1 (41.1-54.2), P = 0.01) and ADP (AUC: 5.8 (3.8-7.3) vs. 8.9 (7.9-12.2), P = 0.002) when measured with AUC  for TRAP, ADP and CRP did not differ between patients pre- and post dialysis. There was no difference between the maximum reached effect and AUC on platelet activation when comparing patients pre- and post dialysis (data not shown).The aim of this study was to investigate the relation between platelet function and kidney failure in patients with end stage renal disease and cardiorenal syndrome using a flow cytometer based, functional platelet assay. We show that P-selectin expression after stimulation with ADP, CRP and TRAP is lower in patients with chronic kidney disease as compared to healthy controls. Furthermore, we demonstrate that the EC50 was not different between groups. This means that platelet sensitivity itself is not affected for the different agonists, but the maximal platelet response is significantly lower.Platelets were activated with 3 different stimuli. We chose for the agonists TRAP, ADP and CRP, which stimulate the three major physiological platelet activation pathways. TRAP activates the thrombin receptor Proteinase Activated Receptor 1 (PAR-1) on platelets. ADP is normally present in platelet dense granules. Upon platelet activation, ADP is released to activate nearby platelets via the P2Y receptors. CRP activates the receptor glycoprotein VI, the major collagen receptor on platelets. So, all 3 stimuli are of physiological importance.P-selectin is found in the α-granula of platelets. A deficiency in α-granula could lead to ineffective haemostasis. Two different explanations are possible for the deficient platelet α-granula release found in chronic kidney disease. This could be due to depletion of α-granula itself, or due to a deficiency in the release of α-granula. An impaired α-granule release has already been reported in uraemia. This isin vitro artifacts, platelet isolation and are dependent on VWF or hematocrit. In our functional assay there is no role for VWF and hematocrit. Moreover, since fresh whole blood was used, and samples were fixated subsequent to stimulation, in vitro platelet activation was negligible. We couldn’t find an immediate effect of haemodialysis, but long term dialysis and classical risk factors for athero-vascular disease could all be studied with this assay. Larger populations should be studied in order to find the factors influencing platelet reactivity in vivo.The clinical bleeding tendency in uremic patients received much attention. Haemo- In our study, aspirin did not suppress the expression of P-selectin on platelets. Considering the fact that aspirin function is related to inhibition of tromboxane formation and does not influences release of granules, this is an expected result. Moreover, our finding is in accordance with a study by Stumpf et. al., in which P-selectin expression on platelets did not show a difference between patients taking aspirin compared to non-aspirin users. Furtherin vitro artifacts . In our assay platelets are not isolated. The incubation in whole blood under standardized condition and the subsequent fixation step makes in vitro artifacts unlikely. When repeating the assay within healthy subjects at different blood collection moments, we find high reproducibility. Moreover, this assay can be used in routine clinical practice.We here demonstrate that the flow cytometry based platelet activation assay can be used in clinical practice to study variables influencing platelet response in patients with renal failure. The assay is based on incubation with different agonists in whole blood and subsequent fixation. Platelets are sensitive for In conclusion, we found that patients with chronic kidney disease show reduced platelet reactivity in response of ADP, TRAP and CRP compared to controls. The defect is probably due to an α-granule defect. Further investigation is required to determine a correlation between platelet reactivity and both renal function and the high mortality risk of patients with chronic kidney disease.The authors declare that they have no competing interests.ERB participated in design of the study and interpretation of data, and contributed to drafting of the manuscript. RLJ participated in design of the study and in the performance of flow cytometry analysis, performed the statistical analysis and critically revised the manuscript. DW and LC carried out the FACS analysis, and participated in the statistical analysis of data and drafting of the manuscript. CAG, LAB and MR participated in the design of the study and critically revised the manuscript. RF designed the study, supervised its conduct and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/127/prepub


Background. Arterial hypertension in renal transplant recipients (RTR) is associated with increased morbid mortality. In the general population, home blood pressure monitoring (HBPM) was found to be superior to office blood pressure (OBP) in identifying true hypertensive patients. The aim of this study was to investigate HBPM for the assessment of blood pressure profile in RTR. Methodology and Principal Findings. We included prospectively 87 stable RTR. Sitting OBP was measured during the outpatient clinic. HBPM was performed by measuring BP every morning and night for 4 days. The accepted limits for the OBP and HBPM, were respectively, 140/90 mmHg and 135/85 mmHg. Patients were classified as “normotensive,” “uncontrolled,” “white-coat hypertensive” and “masked hypertensive”, (OBP below the limit and HBPM above). During the study, 81 patients  were available for analysis. The mean OBP and HBP were 138/83 ± 14/10 mmHg and 133/79 ± 14/8 mmHg; 29% of patients were uncontrolled, 28% normotensive, 21% white coat, and 21% masked hypertensive. Age, glycemia, and number of antihypertensive drugs were associated with hypertension. Conclusion and Significance. In RTR, HBPM is well accepted and better define BP profile since there is 42% discrepancy between OBPM and HBPM. Whether this discrepancy is associated with worst outcome in the long term remains to be demonstrated. Arterial hypertension is prevalent in renal transplant recipients (RTR) and is a powerful predictor of impaired graft and patient outcome . DiagnosThe aim of this study was to evaluate the acceptability of home BP monitoring, to define the prevalence of hypertension with this technique, and to describe the existence of white-coat hypertension and masked hypertension in RTR. We also investigated the risk factors of patients with specific BP profile.Between February and October 2009, we included in this prospective observational study 87 stable RTR. The inclusion criteria were as follow. Patients had to have received a single renal transplant for more than one year and to enjoy a stable renal function during the past 6 months defined as less than 20% of variability of serum creatinine. Immunosuppressive treatment had to be stable during 6 months, especially regarding daily dose and blood concentrations of calcineurine inhibitors (CNI). The patient had to be within targeted CNI blood concentrations, that is, cyclosporine concentrations 2 hours after intake (C2) between 400 and 800 ng/mL; tacrolimus blood trough levels (C0) between 4 and 12 ng/mL. Antihypertensive treatments were monitored and had to be identical for the past 6 months. Patients were not included if systolic BP was lower than 100 mmHg and higher than 190 mmHg.Both office and home blood pressure was measured using a MICROLIFE BP A100 Plus device (Microlife). This automatic device generates a digital display both of systolic blood pressure (SBP) and of diastolic blood pressure (DBP). It has previously been validated and satisfied the criteria of the association for the advancement of medical instrumentation (British Hypertension Society). The device calibration was the same for home and office. The cuff was adapted to the circumference of the arm contra lateral to the arteriovenous fistula (AVF) in patients whose AVF was still functioning. The machine was calibrated to take three measurements.Office blood pressure was first measured by the physician during the clinic. The patients were then asked to have their BP taken once again by a nurse who instructs them on how to perform home BP measurements. BP measurements and information was given by a unique person (CC). Both physician and nurse measurements were obtained while patients were seated, and after they had rested for more than 5 minutes.The instructions given how to perform home blood BP were as follows. Subjects were asked to measure their blood pressure every morning within 1 h of waking and every night (we asked patients to wait about 10 to 12 hours between morning and evening measurements), while they were seated and after they had rested for more than 5 minutes at the time they had taken their blood pressure medication and to record on a specific paper sheet the results for 4 days. We asked patients to wait about 10 to 12 hours between morning and evening measurements. After this period, patients returned their device and the written results were compared to the one recorded in the memory of the device.The home blood pressure of an individual was defined as the mean of all measurements obtained for that person. The mean number of home blood pressure measurements was 8 (at least 4 in the morning and 4 in the evening). There was not significant difference in measurement of HBP in morning and at evening. Thus, we considered that the average of the both measurement of HBP was valid.We used for this study the following definition for controlled and uncontrolled hypertension. For the office measurements, the internationally accepted limit of 140/90 mmHg was adopted. For home BP measurement, we adopted the internationally accepted limit of 135/85 mmHg.Patients were classified in four groups as (i) “controlled” when their BP was below the limit for each of the methods; (ii) “uncontrolled” when their BP was greater or equal to the limit for each of the methods; (iii) “white coat hypertension” when their BP was below the limit of control for HBPM and greater than or equal to the limit for OBPM; (iv) “masked hypertension” when their BP was below the limit for the OBPM and greater than equal to the limit of control for the HBPM.“CPP (Comité de Protection des Personnes)”. All patients gave informed written consent to enter the study.The study obtained ethics approval from the ethics committee of the hospital named P < 0.2 in univariate analysis.Statistical analyses were performed with the SAS JMP software version 5.0.1 for MacIntosh . Characteristics of patients at the time of the study were described using means ± standard deviation or frequencies and compared with the chi-square test, the Fisher's exact test, and analysis of variance, as appropriate. Univariate and multivariate logistic regression were used to determine the odds ratio and confidence intervals. Multivariate analysis was performed after adjustment for variables identified as significant with P value of 0.05 was considered to be statistically significant. Furthermore, we studied the relation between the GFR and measurement error by applying the method as proposed by Bland and Altman [A two-sided d Altman . We asseμmol/L. The immunosuppressive regimens were variable with 88% of patients receiving a CNI as part of the treatment. With regards to the number of antihypertensive at the time of the study, the mean number was 1.5 ± 1, with 16 patients receiving no therapy, 24 patients were taking one medication, 28 patients were on two medications, 11 patients were receiving 3 medications, and 2 patients 4 medications. Among the different antihypertensive medications, 62.8% of treated patients received beta-blockers, whereas angiotensin-converting enzyme inhibitors or angiotensin-2-receptor antagonists were used in 53% and calcium channel blockers in 28.2%. New onset diabetes after transplantation (NODAT) was defined by an HbA1c value higher than 6.5% or ongoing treatment for diabetes. In this population, 4 patients only were receiving antidiabetic treatment consisting in insulin (n = 1) or oral agents (n = 3).We included 87 patients in this study. Of note, only 81 patients were available for analysis: 3 patients did not bring back the device; 3 patients did not perform home BP measurements as indicated. No patient had complains regarding the acceptability of BP measurements. Demographic characteristics of the patients are described in Concerning the other cardiovascular risk factors, 56 patients (69.14%) were treated with lipid-lowering agents. Among them, all received statins and 6 Ezetimib either alone or in combination with statins. We found no discrepancy between the reported BP and reading values within the memory device. We had no phantom recordings. The mean systolic and diastolic BP values for physician were, respectively, 139 ± 14 mmHg and 83 ± 10 mmHg. The respective values were 134 ± 15 mmHg and 82 ± 9 mmHg for nurse BP. These measurements between nurse and physicians were concordant in 73% of patients (with 29% of hypertensive and 44% of normotensive patients). Of note, 19% of the patients were hypertensive with the medical doctor, although they were only 8% with the nurse.r2 = 0.61; P < 0.01). However, using the definitions used . Furthermore, more than 40% of patients with uncontrolled AH received more than 2 drugs to try to control their blood pressure.We then compared the characteristics of patient according to the defined type of BP profile that they presented . UncontrWe found no difference with regard of the presence of hypertension  and the renal function assessed both by serum creatinine and glomerular filtration rate estimated by the MDRD formula.P > 0.05, Fisher test).However, patients with persistent uncontrolled arterial hypertension presented a significantly higher excretion of proteinuria when compared with all the other groups . 26/51 aCardiovascular events are the first cause of death in RTR. Among cardiovascular risk factors, an elevated arterial blood pressure is recognized to be a strong predictor of graft function and patient death , 14–16. We show here that, even though mean BP is relatively well controlled in our population, there is a large discrepancy between home BP and office BP (in up to 42% of patients) with both white-coat and masked AH. Since there is no good marker to discriminate between patients with concordant BP and the 2 previous populations, there is a need to perform both office and home BP.The first question is the relative importance of home BP compared with office BP. First, we found a very good acceptability and compliance for home BP in the renal transplant population. Indeed, we found no phantom recordings. This may be due to the fact that patients were motivated as renal transplant recipients to assess their blood pressure with an extensive explanation of the positive impact both by doctors and the nurses. Stenehjem et al. have already showed that home BP was superior to office BP in estimating BP control in renal transplant patients with deteriorating graft function . It can One interesting finding in our study is that patients with masked BP were also prone to present more often bad control of glycemia. This could be explained by poor compliance of both antihypertensive and diabetic drugs in the population.One other potential advantage of home BP is the detection of both white-coat and masked hypertension. This latter may be important since it entailed an increased risk of ESRD, whereas the risk associated with white-coat hypertension was lower . This maIn our study, we found that uncontrolled BP was associated with higher daily proteinuria excretion. Controlled AH was associated with the lowest value of protein excretion and both masked AH and white AH presented intermediate value. Studies with a higher number of patients and with a longer followup are needed to determine whether one or the other form of AH is associated with bad prognosis.We also wanted to explore whether blood pressure assessment by a nurse would improve the accuracy of the diagnosis. Indeed, the comparison between the value of medical doctor and nurse BP measurements show that the white-coat effect is decreased by the nurse. Even though it is imperfect, we suggest that office BP should be better monitored by a nurse.In conclusion, our study shows that in kidney transplants, home BP measurements is acceptable and may help to better define BP profile. There is a total of 42% discrepancy between office BP and home BP. The high incidence of both white-coat and masked hypertension suggests that the monitoring of RTR treated for hypertension must include home BP self-measurement. Our study demonstrates that proteinuria is higher with uncontrolled BP and show a tendency to be higher in masked hypertension. Followup of a larger population may allow demonstrating the negative effect of all profiles of hypertension. It also remains to be shown that the adaptation of treatment to the results of home BP self-measurement allows better cardiovascular prevention than adaptation of treatment to results of measurements in the physician's office.Our study has several limitations. First, it has been conducted only in a small pilot population. Second, even though it is unlikely, a systematic relationship between timing of antihypertensive drug ingestion and that of BP measurement could explain the better values of home over office BP measurement. Even though patients were asked to have their BP measured at a specific time interval after drug intake, we cannot eliminate this hypothesis since we did not record specifically these data. Another relationship could be proposed between the timing of blood analysis results announcement with the stress induced and the office BP measurement. In this regards, we could have compared the BP at the beginning and at the end of the office visit. Besides, one could argue that the BP threshold of home BP monitoring has not been established and is perhaps different from the general population or the patients under hemodialysis .


Clinical trials have reported reduced cardiovascular events with certain antihypertensive agents at a rate that could not be predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by pleiotropic effects of these agents and modulation of central blood pressures. This review focuses on the mechanisms by which calcium channel blockers exert pleiotropic effects, both alone and in combination with statins and inhibitors of the renin-angiotensin system. The essential role of nitric oxide (NO) in maintaining endothelial function and the relationship between NO and reactive oxygen species are discussed in the context of the etiology of hypertension. The importance of managing global cardiovascular risk is emphasized, as hypertension commonly clusters with dyslipidemia and loss of glucose control. From a mechanistic viewpoint, these risk factors contribute to endothelial dysfunction, oxidative stress, and inflammation in a synergistic fashion. A greater understanding of the mechanisms of actions of these cardiovascular agents may lead to more effective drug combinations, to the benefit of individual patients. Furthermore, by elucidating the biological mechanisms by which cardiovascular risk factors lead to vascular injury, we may highlight common pathways and identify novel therapeutic targets. Blood pressure is a primary and independent risk factor for cardiovascular disease . By convOver the last 10 years, several antihypertensive drug treatment trials have shown an unexpected discrepancy between reduction in brachial blood pressure and observed clinical outcomes. In the Heart Outcomes Prevention Evaluation (HOPE) , the LosIt has been proposed that central aortic pressure may have more pathophysiological relevance than peripheral blood pressure as a marker for the development of cardiovascular disease •, 7. CenObservational studies have shown that the difference between brachial and central arterial pressures can vary by between 2 and 33 mm Hg , 10. FurP < 0.0001), whereas brachial systolic blood pressure was similar between the two treatment arms . Furthermore, central pulse pressure (PP) was associated with total cardiovascular events and procedures and the development of renal impairment . The CAFE study demonstrated that antihypertensive drugs can have different effects on central aortic pressure despite similar brachial blood pressure measurements. The authors of the CAFE study proposed that their study elucidated a plausible mechanism to explain the superior clinical outcomes observed in the amlodipine-based treatment arm of ASCOT. They also speculated that central aortic pressure measurements may provide an explanation for the differences observed in other major outcome trials including LIFE ) ) .4 as cofactors.The signaling molecule NO is produced by the endothelium and has a key role in regulating vasomotor tone. In addition, NO has atheroprotective effects by reducing smooth muscle cell proliferation and migration, adhesion of leukocytes to the endothelium, and platelet aggregation . NO is d2–) .•.2–, NO 2– by uncoupled eNOS. Glucose intolerance is also believed to impair eNOS activity directly through enhanced oxidative stress.Animal models have shown that mice deficient in ROS-generating enzymes have lower blood pressure levels compared with wild-type animals . Further2– generation by NAD(P)H oxidase, which contributes to increased ONOO– formation and uncoupled eNOS activity [In a human tissue study comparing endothelial cells from healthy African American and Caucasian donors, those of African American origin were found to have lower levels of NO despite higher levels of eNOS . This paactivity . These ractivity .Reduced NO bioavailability may partly explain the higher rates of hypertension observed among African Americans compared with Caucasians in various surveys . This ha2–. This adds further support to the theory that agents that enhance NO bioavailability while reducing nitroxidative stress may have important benefits in this population.The finding of a relationship between reduced endothelial-derived NO and increased oxidative stress led to the design of the A-HeFT study  . That trIn summary, the relationship between NO and ROS is strongly implicated in the etiology of hypertension, and drugs that have both antihypertensive and antioxidant properties may be more effective at reducing blood pressure and subsequent pathology. Indeed, improving NO bioavailability may be an important treatment goal in the management of hypertension Fig. .2– [Dihydropyridine (DHP)-type calcium channel blockers (CCBs) reversibly inhibit calcium entry into cardiac and vascular smooth muscle cells by binding to L-type voltage-sensitive calcium channels . This de2– , 30. Thi2– .G-monomethylarginine (L-NMMA). Under identical conditions, other DHP and non-DHP-type CCBs, including nifedipine and diltiazem, failed to reproduce these effects.In animal models, the CCB amlodipine has been shown to increase eNOS activity and its mRNA level in hypertensive rats . In coroIn clinical studies among patients with essential hypertension, nifedipine has been shown to attenuate circulating plasma levels of lipoperoxides and isoprostanes, increase plasma antioxidant capacity, and restore NO bioavailability . In the The safety and efficacy of CCB therapy and its role in reducing cardiovascular events and procedures has been demonstrated in several large clinical studies among patients with and without established cardiovascular disease •, 48•. KHypertension commonly clusters with other cardiovascular risk factors, including dyslipidemia and diabetes, greatly increasing an individual’s risk of an event , 50. FroAlthough controversy remains over the optimal choice of antihypertensive drug therapy, hypertension management guidelines agree that most patients may require at least two antihypertensive drugs to reach the currently recommended blood pressure targets –54. In aA greater understanding of the mechanisms of actions of antihypertensive and lipid-lowering drugs may lead to more effective drug combinations with respect to clinical outcomes. This review focuses on the combination of CCBs with statins and CCBs in combination with drugs that affect the renin-angiotensin system (RAS).P = 0.02) [Both CCBs and statins have been shown to reduce cardiovascular events in large clinical outcome trials •, 48•. A = 0.02) . This isP = 0.03), 3.1 % in the atorvastatin alone group (P < 0.001), and −1.3 % in the placebo group (P < 0.0001). After 28 weeks of treatment, the greatest improvement in small artery compliance remained among those taking co-administered amlodipine and atorvastatin (P < 0.05) [The findings from ASCOT  may be e < 0.05) . The obs < 0.05) •. Indeed < 0.05) .P < 0.05, compared with placebo). The combination of nifedipine and cerivastatin also reduced acetylcholine-induced vasoconstriction by 11 %, but this only reached statistical significance when all coronary segments were analyzed together. After cerivastatin was withdrawn from the market in 2001, the ENCORE study design was modified to compare nifedipine with placebo [P = 0.0088). However, compared with placebo, nifedipine plus background statin therapy did not have a significant effect on coronary plaque volume as measured by IVUS. Together the ENCORE studies add to the evidence that CCB plus statin therapy improves NO-mediated endothelial function [This hypothesis is supported by the results of the ENCORE I study that compared NO-mediated endothelial function among 343 patients with coronary artery disease . Patient placebo . In ENCOfunction , 36.P < 0.05). This was attributed to enhanced eNOS function and expression along with decreased levels of cytotoxic ONOO–. Following low density lipoprotein (LDL) enrichment there was a 60 % reduction in NO production in the HUVEC and an almost twofold increase in ONOO–. Treatment with the combination of amlodipine and atorvastatin partially reversed the adverse effects of LDL, including a 90 % increase in NO and a 50 % reduction in ONOO–. Small angle X-ray diffraction analysis indicated that both amlodipine and atorvastatin are lipophilic and share a common membrane location [From a mechanistic perspective, synergy between CCBs and statins is plausible, as these drugs have complementary chemical structures. Atorvastatin has negative polarity associated with its heptanoic side chain, whereas amlodipine is distinct among the DHPs in having a positive charge on its aminoethoxy side chain , 60, 61.location •. This s1) receptors in vascular smooth muscle cells, promoting vasoconstriction and increasing peripheral vascular resistance. Ang II also stimulates the release of various hormones including aldosterone and vasopressin, which act on the kidneys to increase sodium and fluid retention. Ang II also facilitates norepinephrine release from sympathetic nerve endings and inhibits its reuptake, thereby enhancing sympathetic adrenergic function. The interaction between Ang II and AT1 receptors also activates signal transduction mechanisms that promote oxidative stress, inflammation, cell proliferation, and fibrosis [2– and other ROS, and contributes directly to reduced NO bioavailability and endothelial dysfunction [The RAS has an important role in blood pressure control by regulating blood volume and peripheral vascular resistance. In brief, in response to the release of renin from the kidneys, the circulating substrate angiotensinogen is converted to angiotensin I. The angiotensin-converting enzyme (ACE) in the vascular endothelium cleaves off two amino acids to form the octapeptide, angiotensin II (Ang II). Ang II binds to angiotensin II type-1 (ATfibrosis . Studiesfunction .Blocking the RAS with ACE inhibitors and angiotensin receptor blockers (ARBs) has been demonstrated to improve endothelial function and increase NO bioavailability in mechanistic –67 and c2 receptor mediated upregulation of eNOS [1 receptor-mediated vasoconstriction and AT2 receptor-mediated vasodilation. At the vascular level, Ang II was shown to impair endothelium-dependent NO-mediated dilation attributable to elevated O2– production via AT1 receptor activation of NAD(P)H oxidase. The authors of this study commented that their results may partly explain why impaired coronary flow is associated with upregulation of the RAS [P < 0.05) and increased lumen area. The authors suggested that AT1 receptor antagonists, besides their antihypertensive effects, could also have a role in reducing the development of atherosclerosis [In an animal model using infarcted adult male Sprague–Dawley rats, treatment with the ARB candesartan, enhanced vasorelaxation by increasing NO bioavailability via an AT of eNOS . A compl of eNOS . In an a the RAS . The lonclerosis .P < 0.01) [P < 0.001). However, patients in the ARB group had significantly improved vasoconstrictive response to L-NMMA, whereas no effect was seen in the diuretic and placebo groups [The results of these mechanistic studies were consistent with the results from clinical studies –70. In a < 0.01) . These ro groups . TogetheThere is a growing body of evidence to suggest that DHP-type CCBs and RAS inhibitors have additional beneficial effects when used in combination. For example, in an animal model using Dahl salt-sensitive rats, the combination of CCB plus ACE inhibitor was more effective than either monotherapy in normalizing systolic blood pressure and proteinuria . This stIn clinical studies, the combination of CCBs with an ACE inhibitor versus a CCB alone has been shown to increase flow-mediated dilation, a surrogate biomarker of endothelial function . As prevTogether, these mechanistic and clinical studies demonstrate the pleiotropic effects of the combination of CCB plus RAS blockade on enhanced NO bioavailability and reduced oxidative stress. Understanding the complementary mechanisms of actions of these drugs forms the rationale for combining different antihypertensive agents to enhance their therapeutic effects.This review has explored the pleiotropic effects of CCBs alone and in combination with statins and RAS inhibitors. The mechanisms by which these drugs exert their beneficial effects on endothelial and vascular function have been described, with a particular focus on the effects on NO-mediated vasodilation and oxidative stress. By further elucidating the biological pathways by which these drugs exert their effects, we considered the rationale for choosing optimal drug combinations that will benefit patients at risk. The differential effect of CCBs on brachial and central blood pressure has been explored, along with the future role of central blood pressure as a prognostic marker for cardiovascular disease events. Indeed, clinical hypertension trials have demonstrated the importance of incorporating measurements of central aortic pressure in their study designs. This will provide much needed outcome data to support evidence-based practice. Another important aspect of future hypertension research is the shift towards studying complex disease models. From a mechanistic viewpoint, multiple cardiovascular risk factors act synergistically to exacerbate endothelial dysfunction, oxidative stress and inflammation, thereby accelerating the atherosclerotic process. It is therefore logical that they should be considered together in global risk assessment. By further elucidating the underlying biological pathways and mechanisms that lead to target organ damage in multiple cardiovascular risk factor models, we may be able to define new therapeutic targets and develop novel treatments. Such approaches will continue to require the scientific community to work together to carry out large-scale studies and to link the findings from experimental models with human populations.


Individual health education is considered to be essential in the overall care of patients with type 2 diabetes (DM2), although there is some uncertainty regarding its metabolic control benefits. There have been very few randomized studies on the effects of individual education on normal care in DM2 patients with a control group, and none of these have assessed the long-term results. Therefore, this study aims to use this design to assess the effectiveness of the PRECEDE  education model in the metabolic control and the reduction of cardiovascular risk factors, in patients with type 2 diabetes.An open community effectiveness study was carried out in 8 urban community health centers in the North-East Madrid Urban Area (Spain). Six hundred patients with DM2 were randomized in two groups: PRECEDE or conventional model for health promotion education. The main outcome measures were glycated hemoglobin A1c, body mass index (BMI), blood pressure, lipids and control criteria during the 2-year follow-up period.Glycated hemoglobin A1c and systolic blood pressure (SBP) levels decreased significantly in the PRECEDE group . The decrease levels in diastolic blood pressure (DBP), triglycerides and LDL cholesterol were nonsignificant. PRECEDE increased compliance in all control criteria, except for LDL cholesterol. BMI did not change during the study in either of the two models analyzed.PRECEDE health education model is a useful method in the overall treatment in patients with type 2 diabetes, which contributes to decrease glycated hemoglobin A1c and SBP levels and increase the compliance in all the control criteria, except for LDL cholesterol.NCT01316367ClinicalTrials.gov  Type 2 diabetes mellitus (DM2) is one of the chronic diseases that have increased in prevalence and incidence rates in recent years , and somIndividual health education is considered to be essential in the overall care of patients with DM2, although there is some uncertainty regarding its metabolic control benefits. The PRECEDE  model developed by Green and Kreuter  is one oThe efficiency of the PRECEDE model has been proven in different studies in the health enviroment, such as improving care habits among asthmatic children and improving medication adherence in patients with a chronic disease ,8; howevThere have been very few long-term studies, with randomized controls, on the effects of individual education in normal care in DM2 . TherefoWe conducted an open community effectiveness study in which 21 Primary Care Centers (PCC), in the North-East Madrid Urban Area (Spain), were invited to participate; 13 refused, and 8 PCC were randomized in two arms: Precede Health Promotion Education (PHPE) and Conventional Health Promotion Education (CHPE). The participants at each PCC were randomized by selection from lists of patients with previously diagnosed DM2. Figure Eligibility criteria for patients were: older than 30 years, with previously diagnosed DM2  and the exclusion criteria were: gestational diabetes, patients involved in clinical trials, patients with life expectancy less than 1 year , patients who refused to participate, homebound patients. Patients meeting criteria for inclusion and not meeting any exclusion criteria were invited to participate, and were included after accepting and signing an informed consent form.Visits in both groups included the usual care and individual counseling, based on the CHPE or PHPE models, respectively.The CHPE model was defined according to the recommendations of the Spanish Ministry of Health National Conference on Diabetes Mellitus , which wThe PRECEDE HPE model is a diagnostic tool behavior and therefore the first step in its implementation is to identify the behavior to be analyzed. The model considers the influence of the following three factors on health-related behavior:-Predisposing: factors influencing the patient's motivation to undertake the behavior to be analyzed or encouraged.-Facilitators: factors influencing the level of easiness or difficulty the patient and his/her family have in undertaking a given behavior.-Reinforcing: factors arising after the patient has undertaken the behavior, and which reward or punish it.Nurses in the experimental group had to answer the following question: What does the patient need to change behavior? . After, two behaviors were selected for each patient. The nurses research-practitioners first looked at Predisposing factors that influence the analyzed behavior. Patient's responses and comments were written in two parallel lists: positive (+) and negative (-) factors in patients behaviors that need improvement. Predisposing factors are subjective . Subsequently, factors that facilitate the studied behavior were analyzed. These are objective factors such as patient's skills or availability of resources. Finally, subjective Reinforcing factors (what the patient says after his/her behavior) and objectives .Researchers in the experimental group received training in the PRECEDE model before patients were included in the study. This specific training involved two steps: first they were instructed about the basic, theoretical, and practical concepts involved in the application of the model. Second, they participated in a course on clinical interviews to improve their skills when dealing with patients.Researchers in both groups were subsequently trained in the procedure to be used in the study in three sessions. These covered the criteria for including/excluding patients, collecting variables, collecting biochemical/biological parameters, resolving doubts, and piloting the data collection process with the first histories.The study was carried out during a 2-year follow-up period (2003-2005) and the number of visits was identical for both groups: 10 visits .Baseline data were collected during visits 0 and 1, and during visits 2 to 9 assigned models were applied and the data collected. The PRECEDE model application for each behavior analyzed took 4 visits (sessions), as shown in Figure , associated morbidity , and cerebrovascular accident (CVA), diabetes mellitus complications , and the type of treatment prescribed . In follow-up visits data were collected on various biochemical-biological parameters , and diastolic blood pressure (DBP), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and HbA1c). Blood pressure was measured according to the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (2003) [The data gathered were sociodemographic variables , hygienic and dietary habits, female menopause, tobacco consumption (cigarettes/day), alcohol consumption , physical activity practice (measured in hours per week considering any exercise or activity outside the regular job), self-monitoring of capillary glycemia, foot self-care, medication adherence (was measured using Haynes-Sackett test : 'Most pe (2003) .The primary outcome was HbA1c, lipid levels, blood pressure, BMI after 24 months of follow-up.For an alpha of 0.05, a power of 80%, and in order to detect an reduction of HbA1c of 0.3 percentage units, with a common standard deviation (SD) of 1.15, in the PRECEDE group, the overall sample size required was 462 patients (231 in each arm of the study). Since randomization was by PCC, the sample size had to be larger than if simple randomization had been performed, in order to consider the design effect (DE). The DE was calculated as follows: DE = 1 + (nc - 1) * ICC . The ICC in the present work was deemed to be 0.01. The mean cluster size was assumed to be 30 patients. Given these assumptions, the final sample size required was 596 patients (298 in each arm).t-test or its nonparametric equivalent was used for paired data (Wilcoxon test). Furthermore, Pearson χ2 test was used for the qualitative variables, and McNemar's test was used for paired data.First, a descriptive analysis was carried out for each variable included in this study, involving the mean and SD for the quantitative variables and frequencies with confidence intervals of 95% (95% CI) for the qualitative variables. The Student's The change  was calculated in both diabetological education models, for the following variables: total cholesterol, LDL cholesterol, HDL cholesterol, HbA1c, SBP, and DBP. The effect of the PRECEDE HPE was determined for these variables using the formula: mean value of the change in HPE PRECEDE - mean value of the change in conventional HPE. The covariance analysis methodology (ANCOVA) proposed by Vickers was used to determine the adjusted effect of PRECEDE . The adjIn all instances, the accepted level of significance was 0.05 or less, with 95% CI. All the analyses were carried out using the intention-to-treat principle. Statistical analysis of the data was carried out with SPSS 15.0 .A total of 608 patients were included, of which 51.6% were women, with a mean age of 66.7 years (SD: 14.5), and a natural history of disease mean of 9.1 years (SD: 8.3). A total of 304 patients were assigned to the conventional model and 304 to the PRECEDE model. The two groups studied according to the type of health promotion model were observed to be homogeneous in terms of gender, age, and DM2 evolution time. The baseline clinical characteristics of the two groups, the distribution of morbidity, and chronic complications are shown in Table The PRECEDE model led to a favorable variation in all parameters studied, while the conventional model group failed to achieve an improvement in HbA1c, triglycerides, or SBP, which showed a slight increase Table .p < 0.01), and the decrease in DBP, triglycerides, and LDL cholesterol was nonsignificant. Furthermore, the total cholesterol remained unchanged  in the PRECEDE model. Furthermore, SBP decreased by 3 mmHg , metabolic control (HbA1c <7% and LDL cholesterol <100 mg/dl) (p = 0.02), SBP <130 mmHg (p = 0.02), DBP <80 mmHg (p = 0.01), BP control (<130/80 mmHg) (p < 0.01), and global control (metabolic and BP) (p = 0.02). Nevertheless, it was not significant for the criterion LDL <100 mg/dl and BMI <25 Kg/m2 , BP control (SBP <130 and DBP <80), or overall control (metabolic and BP <130/80 mmHg), indicating that our results cannot be compared.However, on comparing the increase in the proportion of patients with metabolic control in the PRECEDE model obtained in our study with those of transversal studies carried out in primary healthcare, such as the one by Spann et al , we wereThe increase obtained in the proportion of patients with metabolic, blood pressure, and overall control after the application of PRECEDE model is relevant and suggests that there is a need to complement pharmacological treatments with lifestyle modification strategies like the one proposed by the PRECEDE model.The most important limitation of this work is the nature of non-blind experimental studies, with the possibility of bias during response measurement, as researchers know which patients are members of the experimental group. Although, this bias is improbable because measurement of responses was objective, as it was based on results of analytical determinations. However, we believe that there could have been a possible Hawthorne bias effect, with a change in the behavior of the subjects owing to the knowledge that they are being studied. This would have had the same effect on both the groups, because the follow-up of the patients was stricter than normal in the two HPE arms, and they were all well aware of their participation in an experimental study when they signed the consent. A virtue of the study was that there were few losses, indicating that there was no selection bias owing to selective losses and that the analyses were carried out according to the intention-to-treat principle.As a result of all the above-mentioned factors, it can be concluded that the PRECEDE health promotion model is a useful method in the overall treatment of DM2 patients, because it contributes to significant decrease in HbA1c and SBP levels, as well as helps in increasing the compliance with all the control criteria, except for LDL cholesterol. Our findings indicate that further studies are necessary to substantiate these benefits. If they are confirmed, then the impact of the PRECEDE model should be evaluated in terms of cardiovascular morbimortality.The authors declare that they have no competing interests.MASF conceived of the study and participated in its design and perfomed the statistical analysis and drafted the manuscript. FJAB, JCAH, CBL drafted the manuscript and made substantial contributions to the analysis and interpretation. CMM participated in the design and coordinated the research group. ECSP, BRS helped in the statistical analysis and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/267/prepub