Complementary and alternative medicine deserves scientific scrutiny as patients with glaucoma often lose vision despite adequate medical or surgical treatment. Most glaucomatologists abstain from recommending alternative medicine as there is little evidence to support most of the recommendations for complementary and alternate management (CAM) use in glaucoma. Megavitamin supplementation has not been shown to have a long-term beneficial effect on glaucoma. In a glaucomatous eye, a very modest benefit of IOP-lowering may be offset by the temporary elevation in IOP that accompanies exercise. There is little evidence to support the use of special diets, acupuncture, relaxation techniques, or therapeutic touch for the treatment of glaucoma. Marijuana can have a profound lowering of IOP, but the low response rate, short half-life, and significant toxicity are strong indicators that it is not an appropriate therapeutic agent. Future research must be carried out to document the effect of CAM not only on IOP, but also on perimetric tests or other objective parameters, such as ocular blood fow and nerve fiber layer thickness.How to cite this article: Bhartiya S, Ichhpujani P. Complementary and Alternate Management of Glaucoma: The Verdict so Far. J Curr Glaucoma Pract 2014;8(2):54-57. Increasing insights into glaucoma pathophysiology have opened newer vistas of therapeutic approaches, most of which are as yet empirical or investigational, including agents that can improve blood fow to the eye and reduce oxidative stress. With increasing emphasis on lifestyle modifications for combating disease, and a holistic approach to a healthier body, more and more people, patients and doctors alike, have been found to be receptive of CAM. In fact, as many as 5 to 10% of glaucoma patients reportedly use CAM, with almost 60% using more than one modality.2 Interestingly one study reported that more than 60% of patients using CAM do not divulge these details to their doctor, while another reported that 72% of these patients did actually discuss details with their treating ophthalmologist.3 This may potentially put the patients at risk, since the information sourced online and through peers is not always reliable, and the hazards of self-medication well-known. It is important, therefore that glaucomatologists offer advice to patients about the evidence and potential risks of CAM therapies.The National Center for Complementary and Alternative Medicine defines alternative medicine as ‘… those treatments and healthcare practices not taught widely in medical schools, not generally used in hospitals, and not usually reimbursed by medical insurance companies.'This article aims to bring together the currently available evidence, most of which remains empirical and anecdotal in nature.The IOP-glaucoma-optic nerve damage paradigm remains open ended for now. Almost 90% of patients with elevated IOP never develop damage to the optic nerve, while more than one-third of patients with POAG, never have documented elevations in IOP. Also, glaucomatous nerve damage has been known to progress despite good IOP control. There is sufficient evidence, therefore, to indicate that glauco-matous optic nerve damage is multifactorial, vascular-ischemic factors being an important contributory element.Current glaucoma therapy, however, is only directed toward IOP reduction. Nonpressure-dependent risk factors are also getting considerable attention in glaucoma management, but the disease modifying capability of these approaches are yet to find widespread clinical application. CAM, for now, is an attempt to bridge this lacuna.Complementary and alternate management becomes increasingly relevant for end stage glau comas, normal ten sion glaucomas, and those patients who continue to progress despite good IOP control. Glaucomas associated with vasospastic phenomenon are also potential candidates for CAM.2 However, for the purpose of this review, we would broadly classify the available CAM modalities into lifestyle modification, and supplementary therapeutic options.Rhee et al considered nine areas as complementary and alter native for glaucoma: herbal remedies, acupuncture, homeo pathy, faith healing, meditation, megavitamin therapy, therapeutic touch, exercise, and dietary modification .Lifestyle ModificationExercise: Aerobic exercise has been reported to cause lowering of IOP, while other authors have reported that isometric exercise like lifting weights may produce a small IOP increase during exertion.4 Lower levels of physical activity were associated with lower OPP.5 IOP spikes have been noted following rigorous exercise in pigmentary glaucoma, following a burst of pigment release.6Yoga and meditation: Meditation is known to help patients cope with disease better and have a positive impact on their quality of life. Given that both the diagnosis and the management of glaucoma have a deleterious effect on the quality of life of the patient, it may be presumed that both yoga and meditation can help the patient cope with the disease better. However, it is essential to remember that there is evidence that certain yoga postures, especially the inverted position (like Shirshasana) can lead to an IOP spike.7Scuba diving and bungee jumping: These adventure sports should be avoided by patients of glaucoma, especially advanced disease, because of resultant IOP spikes. Increased IOP has been explained with raised episcleral venous pressure or increased choroidal volume due to vascular engorge ment.8Stress: The deleterious effects of stress are manifold, and glaucoma is no exception. Prolonged stress can result in endogenous cortisol and catecholamine release which may increase IOP.9 If a patient with stable disease develops a dramatic rise in IOP or deterioration of visual function, it may be prudent to ask them about potential psychosocial or environmental stress factors. Meditation, biofeedback and relaxation techniques may help manage stress better.Necktie: A tight necktie may increase IOP in susceptible individuals by increasing the venous pressure. There is evidence that the IOP is restored to baseline by homeostatic mechanisms over 15 minutes.10Caffeine: A typical cup of coffee may result in a 1 to 4 mm Hg rise in IOP that lasts for at least 90 minutes. It is therefore recommended that glaucoma patients restrict their consumption to less than 200 mg of caffeine per day.11Alcohol: Alcohol consumption has been variably related to dose-related IOP reduction which may last for several hours through temporary osmotic effect. Beer or water consumption, in large quantities, is known to increase IOP significantly due to volume overload.11 Since red wine is rich in antioxidants, its role in neuroprotection has generated considerable interest. Its use may be advocated with the caveat that alcohol does increase the risk of liver disease.Musical instruments: A person playing high wind musical instruments (e.g. Saxophone) can have two-fold increase in his IOP from baseline level for short duration.12Sleeping position: How patients sleep at night may pose another preventable risk factor in glaucoma. An increase in IOP has been noted when patients are positioned in the supine position as compared to an upright position. These differences may be even more pronounced in patients already diagnosed with normal-tension glaucoma. A recent study found that an action as simple as having the patient sleep at a 30° incline may reduce night time IOP by up to 20% in some patients.13 Sleeping with two or three pillows may boost the effects of other glaucoma therapies.Dietary SupplementsDietary anti-oxidants: Red wine, dark chocolate, cocoa, green tea, curcumin, glutathione, n-6 to n-3 polyunsaturated fatty acid, are credited with anti-oxidant, and therefore potentially neuroprotective, abilities.11 There is however, scant evidence to prove their beneficial effect. Also, the quantities required to have a beneficial effect may be difficult to consume.Marijuana: The reduction in IOP due to reduced aqueous production is attributed to Delta-9-tetrahydrocannabinoid found in marijuana. This IOP lowering is for short lived, and one needs to smoke marijuana every 3 hours for 24-hour IOP control.14 Additionally, marijuana may lower systemic blood pressure and could potentially decrease ocular perfusion. Since it has hallucinogenic and addictive predilection, its use in glaucoma therapy remains unacceptable till such time that an analog without these deleterious effects becomes commercially available.Gingko biloba: The main components of the Gingko biloba leaf extract (GBLE) are favonoid glycosides and terpene lactones, and are credited with improving pre-existing visual field loss in some patients with normal tension glaucoma, by vasoregulatory mechanisms.15 Its multiple beneficial actions, reportedly include increased ocular blood fow, antioxidant activity, platelet activating factor inhibitory activity, nitric oxide inhibition, and neuroprotective activity. GBLE also has a mild blood-thinning effect, synergistic with aspririn, and may be a rheological modifer of blood fow. However, its use must be under medical supervision, especially on aspirin or warfarin analogs, so as to prevent bleeding diathesis.Lycium barbarum (Wolfiberry): Studies have shown that L barbarum extract may be a potential candidate for the development of neuroprotective drug against the loss of RGCs in glaucoma.15 Although the neuroprotective effect of L barbarum polysaccharides on the degeneration of retinal ganglion cells in ocular hypertension or the secondary dege neration of retinal ganglion cells after partial optic nerve transection has been shown histologically, its effect on preserving visual function is still uncertain.Bilberry: Bilberry extracts contain high quantities of antho-cyanin, a favonoid with antioxidant properties and have received considerable attention in the recent past as an attractive adjuvant to conventional therapy.11Salt: There is anecdotal evidence that supplementary salt can help combat vascular dysregulation, by an increase in syste mic blood pressure. This approach is contraindicated for patients with comorbidities like coronary artery disease which would be exacerbated by an increase in systemic blood pressure. Increasing blood pressure may be protective against the blood pressure ‘dips' that occur overnight, especially in normal tension glaucomas.16Omega-3 fatty acids: Omega-3 fatty acids are credited with promotion of vascular health. There is anecdotal evidence that omega-3 FAs may have a therapeutic benefit in glaucoma patients, despite the mild reduction in systemic blood pressure. This may be attributed to a stabilization of ocular blood fow, and not increase or decrease in the blood pressure per se.17Vitamin C: The anti-oxidant property of ascorbic acid has led to considerable interest in its possible role in glaucoma therapy. While low- and high-dose supplementary consumption of vitamin C has been variably found to be associated with decreased odds of glaucoma, serum levels of vitamin C do not correlate with glaucoma prevalence. Aside from a temporary osmotic effect from high dose intravenous ascorbic acid, there is no evidence that megavitamin supplementation has a beneficial effect on glaucoma.318Alternate Systems of MedicineIt is impossible to draw reliable conclusions from available data to support the use of acupuncture or acupressure for the treatment of glaucoma.Acupuncture: The underlying principle of acupuncture is that disorders related to the fow of Chi  can be prevented or treated by stimulating the relevant points on the body surface. Its use in glaucoma however remains empirical, and with no evidence regarding its efficacy.Ear acupressure: Ear acupressure as a method of sen sory stimu lation has been proposed to have a role in neuro-protec tion through regulating nerve growth factor and brain-derived neurotrophic factor and their receptors, thereby encouraging the survival pathway in contrast to the pathway to apoptosis.20 Evidence to its efficacy, however, remains unavailable.Therapeutic touch: Therapeutic touch is based on the ability of its practitioners to manually manipulate a patient's ‘human energy field.' A well-designed study of 12 therapeutic touch practitioners found that these practitioners were unable to detect an individual's energy field.21 There has been no study of the possible effect of therapeutic touch in patients with glaucoma.Because of ethical considerations, randomized control trials comparing CAM alone with standard glaucoma treatment or placebo are unlikely to be justified since conventional IOP lowering modalities are established standards of care. Clinical practice decisions regarding CAM therefore will have to rely on the judgment of the glaucomatologist as well as patient preferences, with communication between the two being key. It is incumbent upon the treating physician to emphasise to the patient that CAM is merely an adjuvant, and not a substitute for glaucoma medication, in the current scenario. The safety of CAM therapies is an important issue. There is widespread belief in the general public that CAM therapies are ‘all natural' and therefore harmless. However, commonly used alternative therapies can have significant adverse effects.


Diabetes increases the risk of heart failure but the underlying mechanisms leading to diabetic cardiomyopathy are poorly understood. Left ventricle diastolic dysfunction (LVDD) is one of the earliest cardiac changes in these patients. We aimed to evaluate the association between LVDD with insulin resistance, metabolic syndrome (MS) and diabetes, across the diabetic continuum.Within a population-based study (EPIPorto), a total of 1063 individuals aged ≥45 years  were evaluated. Diastolic function was assessed by echocardiography, using tissue Doppler analysis (E’ velocity and E/E’ ratio) according to the latest consensus guidelines. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score.The HOMA-IR score correlated to E’ velocity  and E/E’ ratio . There was a progressive worsening in E’ velocity (p for trend < 0.001) and in E/E’ ratio across HOMA-IR quartiles (p for trend <0.001). Individuals in the highest HOMA-IR quartile were more likely to have LVDD, even after adjustment for age, sex, blood pressure and body mass index . From individuals with no MS, to patients with MS and no diabetes, to patients with diabetes, there was a progressive decrease in E’ velocity , higher E/E’  and more diastolic dysfunction .HOMA-IR score and metabolic syndrome were independently associated with LVDD. Changes in diastolic function are already present before the onset of diabetes, being mainly associated with the state of insulin resistance.The online version of this article (doi:10.1186/s12933-014-0168-x) contains supplementary material, which is available to authorized users. Subclinical left ventricle diastolic dysfunction (LVDD) is common in the community  and is rEpidemiological studies have associated diastolic function with aging, hypertension and myocardial ischemia . BesidesMore recently, it was suggested that changes in diastolic function precede the onset of diabetes, being already present in pre-diabetic patients ,13, whiccontinuum.In this study, our aim was to evaluate, at the population level, the association between insulin resistance and LVDD in different stages of the diabetic Participants were selected within the first follow-up of a cohort, representative at baseline of the adult population of Porto, Portugal — the EPIPorto cohort study. In 1999–2003, the cohort assembly was made by random-digit dialing, using households as the sampling frame, followed by random selection of one person aged 18 years or older in each household. Refusals were not substituted within the same household. The proportion of participation was 70%. At baseline, 2485 participants were recruited. Between October 2006 and July 2008, participants aged 45 years or over were eligible to a systematic evaluation of parameters of cardiac structure and function, which included a cardiovascular clinical history, physical examination, detailed anthropometric evaluation, collection of fasting blood sample and a transthoracic echocardiogram. Among 2048 cohort members in the eligible age range at this time, 134 (6.5%) had died, 198 (9.7%) refused to be re-evaluated and 580 (28.3%) were lost to follow-up (unreachable by telephone or post). From this analysis we excluded 73 patients with previous myocardial infarction, percutaneous or surgical revascularization, prior cardiac surgery or significant (moderate to severe) valvular heart disease. Patients with type 1 diabetes (n = 6) were excluded from the analysis.Written informed consent was obtained from all the individuals and the local ethics committee  approved the study. The investigation conforms to the principles outlined in the Declaration of Helsinki.2 and central obesity as waist circumference >102 cm in men and >88 cm in women. Metabolic syndrome was defined according to the American Heart Association updated National Cholesterol Education Program Adult Treatment Panel III (AHA/NCEP) criteria [Hypertension was defined as systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥ 90 mm Hg at the time of the visit (mean of 3 readings) or use of antihypertensive medication. T2DM was defined as fasting blood glucose ≥126 mg/dl or the patient’s self-reported history of diabetes or use of diabetes medications. Hypercholesterolemia was defined as total serum cholesterol ≥220 mg/dl or the use of lipid- lowering treatment. Obesity was defined as body mass index (BMI) ≥ 30 kg/mcriteria . Althougcriteria .continuum: individuals with no MS, patients with MS without T2DM and patients with T2DM.MS was diagnosed if any 3 of the following were present: central obesity (WC 102 cm in men and 88 cm in women), raised triglycerides (≥150 mg/dL or fibrates intake), reduced HDL-C , raised blood pressure (SBP ≥ 130 mmHg or DBP ≥ 85 mmHg or anti-hypertensive treatment) or raised fasting plasma glucose (FPG ≥ 100 mg/dL or previously diagnosed T2DM). We defined 3 populations of interest in the diabetic A fasting venous blood sample was obtained in the morning for measurement of glucose, total cholesterol, LDL, HDL, triglycerides and high-sensitivity C-reactive protein (by immunonephelometry). For insulin measurement the blood was immediately centrifuged and the plasma stored at −20°C, for later measurement. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score in subjects without a history of T2DM before inclusion into the study. The HOMA score was calculated from the formula [All echocardiographic studies were acquired using the same equipment (Hewlett-Packard Sonos 5500). Images were stored on videotape for posterior offline analysis by two experienced cardiologists, blinded to clinical data.Cardiac chambers dimensions, volumes and left ventricular mass were measured according to current recommendations , and indnptrend command, which is an extension of the Wilcoxon rank-sum test. Univariate and multivariate logistic regression analysis was performed to predict the presence of LVDD. The variables included in the multivariate model based on previous knowledge were age, gender, systolic blood pressure and BMI. An interaction term was added to the model to assess effect modification by sex, which was not confirmed.Statistical analyses were performed using STATA version 12 . Data are expressed as mean ± standard deviation for quantitative variables with normal distribution, as median and 25th and 75th percentiles (P25-P75) for variables with non-normal distribution or as number (n) and percentage (%) for categorical variables. Pearson coefficient (r) was calculated to assess the correlation of two normally distributed continuous variables and the Spearman correlation (ρ) was used when the variables were non-normally distributed. The trend across categorical variables was tested with the In this study, 1063 individuals were included, 38% were male, with a mean age of 62.4 ± 10.6 years. The prevalence of MS according to the AHA/NCEP criteria was 41.8% and 11.9% had diabetes. Only 16 patients had T2DM without fulfilling the criteria of MS. Table The HOMA-IR score was inversely correlated to lateral E’ velocity  and positively correlated to E/E’ ratio . According to HOMA-IR quartiles, higher insulin resistance was associated with lower E’ velocity and higher E/E’ ratio, as shown in Table We observed a stepwise increase in HOMA-IR score according to the grades of diastolic function. HOMA-IR score increased from 0.95 (P25-75: 0.56-1.69) in individuals with normal diastolic function, to 1.30 (P25-75: 0.70-2.03) in patients with grade I diastolic dysfunction and to 1.59 (P25-75: 0.83-2.41) in patients with moderate/severe diastolic dysfunction (p < 0.001).Table First, we observed a significant increase in HOMA-IR score from patients without MS  to patients with MS without T2DM  and to patients with MS and T2DM , p < 0.001.Patients with MS or T2DM showed lower E’ velocity and increased E/E’ ratio. Furthermore, as shown in Table The prevalence of diastolic dysfunction was 16.3% in the patients without MS, 32.6% in patients with MS and no T2DM and 36.6% in patients with MS and T2DM  from individuals without MS, to patient with MS without T2DM and to patients with fully established T2DM. Metabolic syndrome was significantly associated with increased risk of diastolic dysfunction, independently of age, blood pressure and body mass index.continuum, including in pre-diabetic patients [In most patients with glucose metabolism disturbances, insulin resistance is the key pathophysiological mechanism. In this study we found that individuals with higher insulin resistance had worse diastolic function parameters and a significantly increased risk of LVDD, which was independent of other determinants of diastolic function. Until now, few other studies have analyzed the association between insulin resistance and changes in cardiac function, namely with diastolic dysfunction. In a group of selected non-diabetic patients undergoing elective coronary angiography, Dinh et al. also found that insulin resistance was independently associated with LVDD  and the patients ,13. AltoMetabolic syndrome, also known as insulin resistance syndrome, is common, affecting more than 20% of the adult population of United States and Europe . Insulincontinuum, it is suggested that diabetes can affect cardiac structure and function in the absence of changes in blood pressure or coronary artery disease, a condition called diabetic cardiomyopathy [At the other end of the diabetic myopathy ,37. In hmyopathy . In our myopathy  and beyomyopathy , resultimyopathy .Subclinical LVDD is recognized as an important predictor of heart failure  and longAll these data suggest that the deterioration of diastolic function is already present in an early phase of glucose disturbance metabolism, before the onset of diabetes, being mainly associated with insulin resistance and not only with sustained hyperglycemia. Interestingly, several studies have shown that insulin resistance, with or without diabetes mellitus, predicted incident heart failure independently of other established risk factors ,43,44. OFuture research will determine if the administration of drugs that increase insulin sensitivity can improve myocardial structure and function, particularly diastolic function. Recently, in animal models of insulin resistance, metformin reduced myocardial fibrosis, attenuated cardiac remodeling and the progression to heart failure ,47. ThisFinally, both insulin resistance and metabolic syndrome are closely associated with obesity. Recent data have demonstrated an independent association between LVDD and obesity , especiaStrengths of this study include the relatively large sample of individuals from the general population without other cardiac diseases and the contemporaneous assessment of cardiac diastolic function using tissue Doppler and using the integrated consensus criteria for diastolic dysfunction evaluation . The latThe main limitation is the cross-sectional design, which partially limits comments on causality, as this would be more robust in a prospective design. Although we have excluded patients with clinical signs of coronary artery disease, we did not perform any stress test to exclude myocardial ischemia, which is one determinant of diastolic dysfunction. In this study, patients were not submitted to oral glucose tolerance test. Finally, detailed analysis of left ventricle function using new strain and strain rates techniques was not performed in this study.Insulin resistance and metabolic syndrome are associated with diastolic dysfunction independently of age, blood pressure and body mass index. These data suggest that subclinical changes in myocardial diastolic function are already present before the onset of diabetes, being associated mainly with the state of insulin resistance and not only to sustained hyperglycemia. Future research will determine if improving insulin resistance using insulin-sensitizers or lifestyle changes can improve diastolic function.


Upper gastrointestinal bleeding (UGIB) is a frequent cause of emergency department admission. It can be caused by a wide spectrum of pathologies, some of which carry clinically significant morbidity and mortality. To stratify the risk and plan the level of care at admission at Emergency Department is challenging. Several risk factors for adverse outcomes are known and different risk scores are developed and applied to stratify these patients. It is unclear if any of these tools are sufficiently predictive to guide emergency physicians' decisionsTo evaluate independent clinical and laboratory variables associated with need for organ support and consequently admission to the Emergency Room. To study the adequacy of AIMS65 and Glasgow-Blatchford Bleeding Score (GBS) in an emergency setting.A retrospective cohort study was conducted in all patients with endoscopically confirmed UGIB admitted in an Emergency Room at tertiary, university hospital between January 2010 and September 2014. Need for organ dysfunction support was defined as need for endotracheal intubation, blood, platelets and coagulation factors transfusion, mechanical ventilation and vasopressor support. Association of independent predictors with need for organ dysfunction support was studied through logistic regression models. Accuracy of risk scores AIMS65 and GBS to predict need of organ dysfunction support was assessed by the area under the curve (AUC).A total of 504 patients presented with UGIB to the Emergency Room during the study period; of those 201,  were included in the study. A total of 44 patients died for an overall mortality rate of 21,9 % and 155 patients  needed organ dysfunction support. On multivariate analysis, ischemic cardiopathy, chronic kidney disease, raised urea and low hemoglobin were found to be independent predictors for need of organ dysfunction support in this population.Risk scores AIMS65 and GBS were found to be both predictors for need of organ dysfunction support and AIMS65 had a higher accuracy in detecting these patients  than GBS . The four variables found in our study together showed more accuracy to predict need of organ dysfunction support .Referring all patients with evidence of UGIB to the Emergency Room may be unnecessary and can prove to be costly and overwhelming to the capacity of the ER. AIMS65 and GBS may be a useful risk stratification tool to determine the level of care in ED, but the accuracy can be improved with new clinical and laboratory markers.


The Italian Ministry of Health decided to introduce community professional services in 2010. This trial provides an opportunity to evaluate the outcomes of a new professional pharmacy service: Italian Medicines Use Review (I-MUR) aimed at reducing the severity of asthma and its associated costs.This is a cluster randomised controlled trial of the I-MUR service. Data will be collected over time before, during and after pharmacists’ intervention. Fifteen Italian regions will be involved and it is aimed to recruit 360 community pharmacists and 1800 patients. Each pharmacist will receive training in medicines use review, recruit five patients, administer the Asthma Control Test and provide the I-MUR service. Pharmacists will be allocated to different groups, one group will be trained in and provide the I-MUR service immediately after completion of the baseline ACT score, the other group will receive training in the I-MUR and provide this service three months later. Group allocation will be random, after stratification by region of Italy. The I-MUR service will involve gathering data following each patient consultation including demographic details, patients regular medications, including those used for asthma, their attitude towards their medications and self-reported adherence to treatments. In addition, pharmacists will identify and record pharmaceutical care issues and any advice given to patients during the I-MUR, or recommendations given to doctors. Pharmacists will upload trial data onto a web platform for analysis. The primary outcome measure is the severity of asthma before, during and after the I-MUR assessed using the Asthma Control Test score. Secondary measures: number of all active ingredients used by patients during and after the I-MUR, number of pharmaceutical care issues identified during the I-MUR, patients’ self-reported adherence to asthma medication during and after the I-MUR, healthcare costs based on the severity of asthma, before, during and after the I-MUR service provision.This study has been developed because of the need for a new way of working for pharmacists and pharmacies; it is the first trial of any community pharmacy-based pharmaceutical care intervention in Italy. The results will inform future policy and practice in Italian community pharmacy.ISRCTN72438848. It is estimated that around 300 million people in the world have asthma with an additional 100 million cases predicted by 2025 [Prevalence of asthma in the European adult population, age 18–44, varies from country to country, with the highest value in Sweden 20.62%) and the lowest in Bulgaria and Lithuania (2%); in Italy it is 6.2% [0.62% and. The total bill includes the costs of direct primary and hospital healthcare (around €55 billion), the cost of loss of production (nearly €42 billion) and the monetized DALYs lost (at least €280 billion).The total cost of respiratory diseases in the 28 countries of the EU alone amounts to more than €380 billion annually with asthma accounting for €33.9 billion [Overall cost of asthma, including individual direct costs, indirect costs and intangible quality of life costs have been related to severity of asthma -6.In 2000, a COI (Cost of Illness) study was carried out in Italy in the frame of the Italian Study on Asthma in Young Adults. The mean annual costs for an asthmatic patient was €741 (95% CI: 599–884) ranging from €379 (95% CI: 216–541) for well-controlled asthmatics to €1,341  for poorly controlled cases that accounted for 46.2% of the total cost [Pharmacists have the potential to improve asthma severity through interventions, which include counseling on inhaler technique, medicine therapy management and medicines use review (MUR) -12.A portrait of the pharmacy profession around the world suggests a wide variation in the practice of pharmacy, not only between countries but also within countries .In England, the Isle of Wight Respiratory project, involved health care practitioners including community pharmacists. The aim was to reduce respiratory death, hospital admission and the cost of respiratory medication. In this study, general practitioners referred patients to their community pharmacist for inhaler technique training. The results showed that reliever therapy costs dropped by 22.7%, emergency admissions due to asthma reduced by 50%, deaths fell by 75% and hospital inpatient costs fell by 66%. A review on the NICE shared database highlighted that the training of health care practitioners carried a cost, which was paid back seven times over with the reduction in cost of bronchodilators within one year of the project .In Denmark, a prospective controlled multicenter study, aimed to improve asthma severity (status) by increasing the participation of pharmacists and promoting cooperation with patients and the patient’s general practitioner (GP). The study recruited 500 asthmatic patients from primary care, and found improvements in asthma symptoms status, quality of life and days of sickness .In Finland, a 10-year asthma program was undertaken from 1994 to 2004 to improve asthma care and prevent asthma costs increasing, using general practitioners, nurses, and pharmacists. The main goal of this program was to lessen the burden of asthma to individual and to society. Pharmacists provided patients with written or oral information on preventers and relievers during 98% of asthma medication purchases, plus gave instruction on inhalation technique to 98% of newly diagnosed asthmatic patients and 34% of patients with existing disease. Pharmacists’ intervention combined with the ones provided by GPs and nurses contributed to reduce the number of days patients were in hospital which fell by 54%; the increasing cost of asthma had stopped and the annual cost per patient decreased by 36% from €1,611 to €1,031 .An Australian multi-site randomised controlled trial compared pharmacist counseling on asthma, asthma medication and associated lifestyle advice with a control group providing usual care. Fifty pharmacies were enrolled and randomly allocated to one of the two groups (randomisation conducted at pharmacy level), the intervention group with 191 patients and the control group with 205 patients. In both groups questionnaires and spirometric testing were carried out at baseline and at six months. The main outcome measure was asthma severity/control status assessed by a tool adapted from the National Asthma Council. The percentage of patients in the intervention group classified as having severe asthma declined from 87.9% to 52.7% (p < 0.01), whilst the change in the control group the change was not significant . These authors used a multilevel logistic regression model to adjust for the difference in asthma severity at baseline and to account for any possible effect from clustering. Both pharmacist groups administered questionnaires and spirometric testing at baseline and six months later; it was found that patients in the intervention group were almost three times more likely to change from the severe asthma category to the not severe category than patients in the control group  .The Medicines Use Review (MUR) service was first introduced in England in 2005 as an advanced service in the community pharmacy contractual framework. The aim of the MUR is to achieve a concordant consultation about medicine-taking by establishing the patient’s actual use, understanding and experience of taking their medicines, with the ultimate aim of improving the clinical and cost-effectiveness of prescribed medicines, reducing medicines wastage and improving patient outcomes through improved adherence .Portlock et al.  conducteAnother study involving 154 patients with asthma receiving an MUR found that the proportion of patients whose asthma was not controlled fell from 59% to 45% (p < 0.01), 30% of patients were referred to their GPs or asthma nurse as a result of their MUR and, of those referred, 70% had a treatment or dosage change .This study is about developing a similar service in Italy where no such services exist. The I-MUR has been designed as a structured interview, supported by a quantitative questionnaire enabling pharmacists to capture in a systematic way a patient’s demographic data, quantity and type of medicines used, their knowledge about the medicines used, their adherence to the medicines, actual complaints , plus any pharmaceutical care issues identified by the pharmacists, the advice given to physicians and to patients, including healthy living advice, using an online platform .The Italian government is considering introducing the I-MUR service, but at present there is no evidence from Italy on the feasibility, acceptability or effectiveness of such a model. Hence there is a need to gather robust data on all aspects of the potential new service to inform service design and delivery.A pilot study was carried out between October 2012 and January 2013, to assess the feasibility of Italian community pharmacists delivering I-MURs to patients with asthma . In thisThis pilot study was carried out in four Italian regions and involved 74 pharmacists who provided the I-MUR to 895 patients during a four-month period, following training . The traFollowing this pilot study, which focused on pharmacists, a second study, conducted between October and November 2013, sought to obtain patients’ feedback and GPs’ views on the I-MUR service provision. All patients who had received the I-MUR service previously were invited to complete a feedback questionnaire. Responses were obtained from 246 patients (27% response rate). The questionnaire found that 50% of patients were neither worried nor had problems with their medicines before having the I-MUR, but 75% of them confirmed that they benefited from the service. Seventy-five percent of patients also indicated they felt involved in all the discussion, 37% confirmed that I-MUR found problems with their medications and 27% agreed that changes were made to their medication after the I-MUR. Half the patients would consider having another I-MUR and 85% would recommend the service to other patients .In Italy no other work has been conducted on asthma involving community pharmacists, therefore this current study is needed to determine whether the I-MUR can contribute to improve asthma outcomes and to demonstrate whether the service provides clinical and cost benefits, as these were not included in pilot work. The study will provide evidence about the practicability and costs of provision and the effectiveness of the I-MUR in asthmatic patients.I.Reducing the severity of asthma as assessed by the Asthma Control Test (ACT) score?II.Optimising the number of medicines (active ingredients) used by patients?III.Identifying and resolving pharmaceutical care issues?IV.Improving patients’ adherence to asthma medications?V.Reducing costs (direct and indirect) related to the reduction of the severity of asthma?Is the I-MUR service provided by community pharmacists in Italy effective in:During this study there will be no risks for patients. Those patients receiving the I-MUR service will be at no greater risk than those receiving usual clinical care. Pharmacists will ask their patient to complete the ACT tool and will provide the I-MUR service. They will not dispense or administer any medications based on the results of the ACT or I-MUR results. Pharmacists will neither be involved in the interpretation of diagnostic tests, nor their results.The activity involved in this study will not expose pharmacists to any risk beyond their normal professional practice.This will be a clustered randomised controlled trial with multiple data collection points.Data will be collected from 360 Italian pharmacists who will provide I-MUR services to 1800 patients over a nine-month period.A standard randomised study design would mean that some pharmacists would not provide the I-MUR service to their patients, in order to form a control group, an approach which could lead to demoralise and disengage pharmacists who will not have the chance to provide the service. In addition, individual pharmacists may differ in their practices, and their patients may be cared for by GPs with different practices. Hence the study design must minimise the impact of any individual pharmacist or GP on the management of asthma. To avoid these problems, it was decided to design a cluster randomised control trial in which pharmacists are randomly allocated to provide the intervention to their patients either early or later during the study period. Randomisation will be at pharmacist level, not at patient level, with each pharmacist representing a cluster and outcome being measured for individuals within those clusters .Data will be collected before, during and after intervention delivery, to assess if timing of the intervention affects the primary outcome: the severity of asthma.Italy is a country with nearly sixty million people and it is divided in 20 regions. Pharmacist participants will be selected from different regions throughout the country to reduce potential impact from North–South climatic variation, which could impact asthma severity. Selected regions include Trentino Alto Adige, Lombardia, Sicilia, Puglia, Sardegna, Piemonte, Valle d’Aosta, Veneto, Friuli Venezia Giulia, Toscana, Emilia Romagna, Marche, Abruzzo, Lazio and Campania. Pharmacists will be stratified by region before randomisation. These geographical areas were identified and selected by the Italian Pharmacists’ Federation following attendance at regional presentations of the study conducted by the principal investigator (PI).To evaluate the outcomes of I-MUR interventions provided by Italian community pharmacists in an asthmatic patient population.Pharmacists will provide the I-MUR service following administration of the ACT at either T0 or T3 depending on group allocation, recording details of all PCIs identified and advice provided during the I-MUR consultation.The I-MUR intervention covers the following areas: patients’ demographics, their regular medications (active ingredients) including those used for asthma, patients’ attitude towards their medications and adherence to treatments assessed with the I-MUR interview, pharmaceutical care issues identified by the pharmacist, pharmacist’s advice given to patients, including healthy living advice, pharmacist’s advice given to Doctors, pharmacist’s own view on the potential benefit to the patient of the MUR service they provided.Following each consultation, pharmacists will be required to enter the results into the web-based template provided, maintaining patient anonymity.An invitation letter and a summary of the study was prepared by the PI and sent to FOFI.FOFI distributed the above information to all community pharmacists in all the identified regions inviting pharmacists to participate in the study.Pharmacists who expressed interest in participating were invited to attend a regional presentation. At the regional presentations, which took place between March and April 2014, the PI outlined the study protocol and the enrollment criteria and participants were given a detailed participant information sheet.The regional team leader collated names of pharmacists who expressed interest over the next three to four weeks and the first 36 who met the inclusion criteria (see below) were selected for study inclusion and invited to the I-MUR training.a private area for private consultation with patients;an internet connection available where the consultation will take place.Pharmacies must havebe qualified and registered with the Italian Pharmacy Board practising in Italy;have at least one year of experience in providing advice to patients;already provide one or more services such as blood pressure monitoring, smoking cessation, cholesterol monitoring, signposting, food intolerance testing., in order to demonstrate advanced consultation skills and experience;be able to attend training sessions.Pharmacists musthave no internet access; orno consultation room.are currently involved in any other clinical pharmacy research project.Pharmacies must be excluded if theyPatients will be identified by the individual pharmacists from their medication history, from their prescriptions, or by referral from GP, according to inclusion and exclusion criteria listed below.be at least 18 years of age;have been diagnosed with asthma, for at least six months before enrolment to the study;have a prescription(s) for asthma medication with R03 as ATC code , or drugs for obstructive airways disease.Patients must:have terminal illness (defined as an advanced stage of a disease with an unfavourable prognosis and no known cure) as identified by the pharmacists through the prescription coding;are currently enrolled in another clinical trial;do not self-administer their inhaler;are not able to communicate well in Italian both written and spoken.Patients must be excluded if theyPharmacists, after having assessed patients’ eligibility for the study, will provide an information letter and consent form to each patient, who will be given an opportunity to consider their participation. All signed consent forms will be retained by the pharmacist in the pharmacy.An academic member of staff at Medway School of Pharmacy, experienced in clinical trials will be in charge of the randomisation process. Pharmacists will be randomly allocated to group A or B. Pharmacists will be stratified by location, prior to randomisation, using computer-generated random numbers. Blinding will not be possible either at pharmacist or patient level because the nature of the intervention requires their full knowledge. However the PI, as assessor of the main outcome measure, severity of asthma, will remain blind throughout. As group allocation will be intrinsic to the data gathered for each patient, in order to maintain blindness, the PI will access the data only after all patients have been followed up at three months  is a patient-completed questionnaire with five items assessing asthma symptoms , use of rescue medications, and the effect of asthma on daily functioning. Each item includes response options corresponding to a 5-point Likert scale, which are summed to yield a score ranging from 5 (poor asthma control) to 25 (complete asthma control). Schatz et al.  found thPharmacists will administer ACT tests to their patients in the pharmacy consultation area allowing patients’ privacy to read the questions and take the necessary time to respond.This will take place in the pharmacy private consultation area. The estimated time for the consultation will be 26 minutes based on phase one experience.Data collected during the I-MUR will include patient demographics, their regular medications (active ingredients) including those used for asthma, patients’ attitude towards their medications and adherence to treatments assessed during the I-MUR interview, PCIs identified by the pharmacist, pharmacist’s advice given to patients, including healthy living advice, pharmacist’s advice given to doctors, pharmacist’s own view on the potential benefit to the patient of the MUR service they provided.Following each consultation, pharmacists will be required to enter the data from each consultation into the web-based template provided, maintaining patient anonymity. This process was developed and tested during earlier work .Data collected at multiple time points will be patients’ responses to ACT, adherence to asthma treatment and number of active ingredients  using SPSS sample power calculation. The ICC represents the correlation between responses of individuals in the same clusters which is a proportion of the total variation explained by variation between clusters  and its Four options were considered Table  all usinIn studies where the important baseline factors seem well balanced, it is likely that any differences in outcome between intervention and control groups are a real effect of treatment, which is one component of the internal validity. Patients’ location, age, gender and ACT score will be collected and compared at baseline. This baseline ACT score will provide information regarding the level/severity of asthma prior to intervention delivery.©) will be exported and analysed using SPSS version 22. Patient location, age, gender and ACT score will be compared at baseline.Quantitative data gathered through the web platform  will also be assessed. It will be possible to compare data before and after the I-MUR intervention for group A and B, separately and combined. In addition findings will be analysed by region.2 will be used for categorical parameters. Outcomes for continuous parameters will be evaluated using repeated measures multivariate ANOVA.A significance level  of 0.05 will be used in all analyses. Between-group differences at baseline will be compared using independent Student’s t-test for continuous parameters and Pearson’s χThe analysis will be conducted in two steps. Step one will represent an interim analysis after the first six months, after completion of T6, by which time all patients will have been followed up for three months after the intervention. Step two will represent the final analysis, which will be conducted at the end of the study after T9.Severity of asthma: before, during and after the I-MUR service provision assessed using the ACT score.Number of active ingredients used by patients during and after the I-MUR service provision, as reported by patients.Number of PCIs identified during the I-MUR service provision, classified using the method of Krska et al.Patients’ adherence to asthma medication during and after the I-MUR service provision, measured using questions embedded within the I-MUR instrument.Cost estimated on the severity of asthma, before, during and after the I-MUR service provision.This study has been developed because of the need for a new way of working for pharmacists and pharmacy in Italy. If the results are positive, the study has the potential to open up a new professional perspective for Italian community pharmacists, providing this is accepted by all stakeholders: Italian medicine control agency , Italian Ministry of Health, Italian general practitioners and hospital doctors.It is also important internationally, as it is one of the largest studies ever conducted in community pharmacy and the first and largest study ever conducted in Italy, involving 75% of Italian regions.This is the first trial of any community pharmacy-based pharmaceutical care intervention to be carried out in Italy. The results of this study will inform future policy and practice in Italian community pharmacy.This is the first study conducted in Italy aiming to assess pharmacists’ contribution to reducing the severity of asthma; it is one of the largest studies conducted in one single country and it introduces a new systematic and quantitative research instrument: I-MUR.The study includes only adults, does not require spirometric testing and will run for nine months. We do anticipate, given the size of the study, that problems may arise, for example, with pharmacist and patient recruitment, resulting in the study being underpowered. However we have taken account of this in our power calculation, by evaluating four possible options based on actual results from phase one. There is also the possibility of a higher drop-out rate than anticipated and, while the study will enable us to assess whether ACT score is a suitable primary outcome measure, this may prove not to be the case.Ethical approval was obtained from the Faculty of Science Ethics Advisory Group for Human Participants on 18th February 2014 (reference number 0281314) from the University of Kent (UK), and in Italy on June 3rd 2014 by the Ethics Committee of Spedali Civili di Brescia (Lombardia region) with reference number NP 1710, which is acting as the reference committee for all Italian participating regions.


The prevalence of hypertension in South Africa has been estimated to be 20% of the adult population with over six million people being affected. Poor adherence to treatment plans lead to inadequate blood pressure control and high morbidity. Many studies have looked at factors contributing to poor blood pressure control in South Africa but few studies actually focus on district hospitals in Kwazulu-Natal in particular, despite the fact that the province has the most heterogeneous population in South Africa.The study was a descriptive cross-sectional study conducted at the chronic outpatient clinic of an urban district hospital involving 370 participants aged 18–90 years.The study showed poorly controlled blood pressure in 58% of the participants. Only 35% knew their blood pressure results on the day of interview and 19.2% were aware of their target blood pressure. Good adherence was self-reported by 95% of the participants, whist 51.4% reported significant side-effects to medication.The majority of patients had poor knowledge about blood pressure and little awareness of their blood pressure reading. These may be precursors to poor blood pressure control and this needs further investigation. A high level of self-reported adherence to medication did not translate into effective blood pressure control. A significant number reported medication side-effects which may have contributed to the poor blood pressure control. The high adherence rate may therefore have been over reported. An objective way to measure adherence will be necessary for future research. Although, largely preventable and modifiable, uncontrolled hypertension has been reported to negatively affect the global population's health, causing cerebrovascular accidents and cardiac diseases.2 It has a major influence in the development of cardiac and vascular diseases. Despite being a highly treatable condition, studies have shown that hypertension remains poorly controlled.3 In addition, the diagnosis, management, and control of hypertension pose a great challenge for physicians and researchers.4Hypertension ‘accounts for greater than 5.8% of the total deaths, 11.9% of the years of life lost, and 1.4% of the disability-adjusted life years worldwide’.5 A number of clinical trials have shown that optimal blood pressure (BP) control can be achieved in most hypertensive patients using multiple antihypertensive medications.6 A retrospective study conducted in community-based settings in the USA indicated that 70% of the population had blood pressure levels that were optimally controlled. This was similar to the National Health and Nutrition Examination Survey (NHANNES) study done between 2007 and 2008, which indicated that 69% of patients in this cohort had controlled blood pressure. This study showed that optimally controlled patients living with hypertension were significantly more likely to be younger and have less co-morbidity.7 A study which looked at uncontrolled hypertension in the United States concluded that the majority of cases were due to systolic hypertension. This report reaffirms the need to assess the extent to which patients are aware of their systolic blood pressure as systolic blood pressure awareness and education is an important component of the interventional programme that is used in the control of hypertension.8Hypertension affects approximately one billion individuals worldwide and fifty million individuals in the United States of America.9 Numerous studies have concluded that poor medication adherence, lack of patient awareness about their target blood pressure levels, physician inertia as well as the presence of drug side-effects should be considered as possible causes of inadequately controlled blood pressure.3Hypertension control has been positively linked to adequate knowledge about blood pressure goals. A recent study done on 7649 participants across Europe showed that poor blood pressure control bears a strong correlation to lack of knowledge of target blood pressure. The study found that 50.4% of participants had controlled blood pressure and 49.4% had knowledge of their target blood pressure.5 An article in Time magazine in 2004 stated that ‘with sub-Saharan Africa's population of 650 million and increasing longevity and westernization, hypertension has now changed from a relatively rare condition to a major problem. This observation necessitated the African Union to regard hypertension as one of the continent's greatest challenges after AIDS’.10 The prevalence of hypertension in rural studies undertaken in sub-Saharan Africa in the 1970s, 1980s and 1990s using the previous definition of blood pressure of 160/95 mmHg found hypertension to be as low as 4.1% in Ghana, 7.0% in Lesotho, 5.9% in Nigeria, and 7.37% in rural Zululand in South Africa.11Adequate assessment and treatment of hypertension has always been a major challenge for public health care workers.12 This number is likely to be even higher in 2012 because of population growth and growing urbanisation.13 In the year 2000, 47 000 deaths in South Africa were attributed to high blood pressure, and elevated blood pressure was the second leading contributory cause of death.14Estimates based on the 1998 demographic survey put the prevalence of hypertension at 11% and 14% of South African males and females respectively. This implies that there were six million hypertensive persons in South Africa.15 The 2011 South African Hypertension Guidelines recommend that the target blood pressure for patients on hypertensive therapy should be below 140/90.16 In patients with major cardiovascular risks such as those with diabetes mellitus, associated clinical conditions or established target organ damage, the optimal blood pressure should be 130/80 mmHg.16A study amongst Durban adults reporting hypertension trends using the WHO criteria of 160/90 mmHg found hypertension to be more common in urban black South Africans of Zulu origin (25%), moderate in white South Africans (17%), and Indian populations (14%), and the lowest in rural black South Africans.17 However, outside of clinical trials, control of hypertension remains disappointing with an estimated 30% of patients on treatment being effectively controlled.18In well conducted clinical trials, antihypertensive drugs either as mono-therapy or combination therapy have been shown to effectively control blood pressure and reduce cardiovascular morbidity and mortality.19 In both high and low income countries, less than 27% and 10% respectively of hypertensive patients have achieved their target blood pressure.19Despite the availability of multiple effective antihypertensive drugs, control of hypertension remains poor.17 In addition, poor treatment adherence, inappropriate prescriptions, therapeutic inertia and unhealthy lifestyle contribute to poor control.21 The 2011 South African Hypertension Guidelines emphasised poor adherence to medication as one of the main causes of uncontrolled blood pressure and was thought to be due to treatment factors, patient factors and illness related factors.16 Other factors identified as contributors to uncontrolled hypertension include sex, age, and race.8 In South Africa, white and Asian individuals have been noted to have better blood pressure control compared to their black counterparts.12 Black individuals also develop hypertension earlier in life, have more severe hypertension related complications and respond differently to antihypertensive medication.22Many reasons have been ascribed for the poor control of hypertension worldwide. Patient knowledge of hypertension also plays an important role in the ability to achieve successful control.12 Women were substantially more likely to be aware of their hypertension than men, 51% and 26% respectively. The population survey also found that 36% of women and 21% of men had hypertension but were not on treatment. Amongst those on treatment, only 18% were controlled. With respect to ethnic differences, black South Africans had the lowest rates of awareness, treatment rates and control of hypertension.12In the first South African Demographic and Health Survey (1998), awareness, treatment status, and control varied substantially between men and women, as well as between different ethnic groups.There is little published data on hypertension control amongst patients attending district hospitals in the KwaZulu-Natal Province, South Africa. The aim of this research was to describe the pattern of blood pressure control amongst patients attending a busy outpatient clinic in an urban district hospital. The specific objectives were to describe the demographic and clinical characteristics, knowledge of hypertension targets, degree of adherence to medication and knowledge of side-effects to antihypertensive medications. Approval for the study was granted by the Bioethics Research Committee of the University of KwaZulu-Natal (UKZN), the postgraduate education committee, hospital management and the KwaZulu-Natal Department of Health. Written consent was obtained from all study participants.This was a descriptive, cross-sectional study done at the chronic outpatient clinic at a busy urban public health district hospital. An average of 1375 hypertensive patients was seen monthly at the outpatient clinic in 2011. A sample size of 370 was selected as being appropriate for an observational descriptive study as confirmed with a biostatistician. Hypertensive patients visiting the outpatient clinic were systematically sampled by selecting every third patient that met the inclusion criteria over a three month period commencing October 2012. Sampling was stopped when the sample size was attained. The inclusion criteria were all patients living with hypertension older than 18 years attending the chronic clinic, and on treatment for hypertension for at least one year. Excluded from the study were pregnant women and cognitively impaired patients. Patients’ clinical records were reviewed and an exit structured interview was conducted with each participant by the principal investigator after the participant had consulted the hospital medical officer. The study tool captured demographic data, anthropometric data and, clinical information from the clinical record. Patients were asked specific questions about their hypertension, co-morbid conditions, and habits. Blood pressure readings from the last two clinic visits plus current blood pressure readings were captured. Poor control was defined as blood pressures greater than 140 mmHg systolic or 90 mmHg diastolic. Patients who had two of the three readings elevated were considered to be poorly controlled. Data was captured and analysed using SPSS Statistics for Window Version 21.0. . Results were summarised by frequencies and percentages  and mean, median, standard deviation and percentiles  as appropriate. Wilcoxon signed rank test was used in analysing the variations and trends between the categorical data.Forty-nine percent of the participants were black South Africans, 25.4% were Indians, 17.8% were Mixed race and 7.6% were white South Africans with their age groups being presented in The study showed uncontrolled blood pressure (BP) in 58% of the participants during the preceding three months. Other determinants of blood pressure control are shown below in p = 0.514). There was no statistically significantly association between blood pressure control and increase in number of antihypertensive medications used (p = 0.527).There was a statistically significant association between side- effects to medication and blood pressure control (p = 0.004). There was a statistically significant association between BP control and ethnic group (p = 0.004).The associations between the various factors contributing towards blood pressure control are shown in 23 However, this degree of control is too low considering the complications of hypertension. Poor blood pressure control translates into increased cardiovascular morbidity and mortality such as ischemic heart diseases which affects the burden placed on health care services in South Africa.The study showed a blood pressure control rate of 41.9% amongst the patients attending a district hospital in Kwazulu-Natal. The control rate was slightly higher than the average rate of 40% that was previously reported in South Africa but consistent with a global control rate of 19% – 54%.p = 0.004.) These further affirm findings of earlier studies which showed highest reported cases to be amongst urban black South Africans and females when viewed along ethnic and gender lines.15The demographics of the study group presented in 24 This study showed that only 19.2% of the participants had knowledge of their target blood pressure and the cross tabulation for the blood pressure control vs. knowledge of target blood pressure did not show a statistically significant relationship (p = 0.585).It has been argued that greater medication adherence and better blood pressure control improves with patients’ knowledge of hypertension.26The self-reported adherence rate of 88.4% does not correlate with the degree of control noted (42%). A high adherence should translate into a well-controlled blood pressure. The cross tabulation between BP control and side-effects indicated that there is a statistically significant association between side- effects reported and BP control. This would suggest that patients who experienced side- effects to drugs may have over reported their adherence rates. This over reporting of adherence is consistent with findings from other studies.27 The significantly higher proportion of side-effects noted in this study was associated with multiple antihypertensive medications and this was statistically significant (p = 0.042).This study showed that 51% of the participants reported side-effects to antihypertensive medications but 60% of these participants could not identify which drugs caused the side-effects. It has been reported that 35% of hypertensive patients will stop taking their drugs in the first six months if they experience a side-effect. Another reported reason for stopping medication was patient dissatisfaction with treatment.This study showed that 70% of the participants were using more than three medications, which is of concern as they constituted the largest percentage of uncontrolled hypertensive patients. These participants would be classified as having resistant hypertension and in South Africa should have been managed at a regional level hospital. The study also showed that 80.3% of the participants had other co-morbid diseases necessitating poly-pharmacy, which increased the possibility of adverse drug-drug interactions.The findings of this study support previous studies which demonstrated that only about 40% of hypertensive patients attain blood pressure control in South Africa. A plan to improve the control of blood pressure from the current 42% to greater than 80% is urgently required. The poor knowledge of blood pressure control and hypertensive targets amongst this cohort of participants should be addressed by clinicians through improved patient education. The high number of reported side-effects to anti-hypertensive medication should alert physicians that prescription practices in hypertensive patients may need reviewing. In addition, quality assurance teams at district level should be encouraged to do regular clinical audits of the management of hypertensive patients and monitor outcomes. Regular monitoring and evaluation of hypertension should be part of routine clinical practice and poorly controlled patients with resistant hypertension must be referred to higher levels of care. This study supports the development and implementation of educational programmes that improve the knowledge of hypertension in patients.Educational intervention aimed at counselling patients about the cardiovascular implications should be instituted. Pharmacists, nurses and doctors managing hypertensive patients should aim to address the gaps in the management of hypertension identified by this study. There is need for future research on patients’ adherence rates using a more objective approach than self-reporting.It is worth mentioning that a degree of bias may exist in this study. Adherence rates may have been over reported as the investigator is a doctor known to patients at the clinic. The predominant age group are elderly with multiple co-morbidities, which might have made hypertension control more difficult. The generalisation of these results should be limited to urban district hospitals and communities with heterogeneous ethnic populations.


In patients with type 2 diabetes, the prognostic impact of an orthostatic rise in blood pressure is not known. Therefore, the aim of this study was to determine the prognostic implications of the diastolic orthostatic blood pressure response in a cohort of patients with type 2 diabetes. We also evaluated associations between different orthostatic blood pressure responses and markers of subclinical cardiovascular organ damage.Office blood pressures were measured in the sitting and in the standing position in 749 patients with type 2 diabetes who participated in the CARDIPP study (Cardiovascular Risk factors in Patients with Diabetes—a Prospective study in Primary care). Diastolic orthostatic hypertension was defined as a rise of diastolic blood pressure ≥10 mmHg and diastolic orthostatic hypotension was defined as a drop of diastolic blood pressure ≥10 mmHg. Recruitment took place between the years 2005–2008, and patients were followed until any of the primary outcome events  occurred or until December 31st, 2014. Measurements of aortic pulse wave velocity and of carotid intima-media thickness were performed at base-line.P = 0.046). Diastolic orthostatic hypotension was found in 31 patients (4.1 %) and was associated with higher values for aortic pulse wave velocity and carotid intima-media thickness, compared with patients with normal systolic and diastolic orthostatic blood pressure response.Diastolic orthostatic hypertension was found in 140 patients (18.7 %) and was associated with significantly lower risk of cardiovascular events (crude hazard ratio compared with patients with normal systolic and diastolic orthostatic blood pressure response: 0.450, 95 % C.I. 0.206–0.987, Diastolic orthostatic hypertension is common in patients with type 2 diabetes, and may be a novel marker for decreased cardiovascular risk in these patients. In patients with type 2 diabetes, orthostatic hypotension is a common clinical finding , which iAs described previously , CARDIPPThe primary endpoint was a composite endpoint of the first non-fatal or fatal event of hospitalization for acute myocardial infarction (ICD-10 code I21), or stroke  or cardiovascular mortality (ICD-10 codes I00–99). Patients were followed until a primary outcome event occurred, or until December 31st, 2014, by linkage to the Swedish Cause of Death and Inpatient registries  using the national personal identification number of each individual patient, thus ensuring coverage of the entire population.Office blood pressure was measured by specially trained nurses . MeasureTo measure aortic PWV, electrocardiogram-gated pulse wave analyses of the carotid and femoral arteries were performed with a Millar pressure tonometer and the SphygmoCor system . The pulse wave transit time was calculated by subtracting the time between the ECG R-wave and the arrival of the pulse wave to the carotid measurement site from the time between the ECG R-wave and the arrival of the pulse wave to the femoral measurement site. The surface distance was defined as the distance between the suprasternal notch and the femoral measurement site, subtracted by the distance between the suprasternal notch and the carotid measurement site. The PWV was calculated by dividing the surface distance with the pulse wave transit time. Applanation tonometry measurements were performed in duplicate, and reported as means of the two measurements. Measures of PWV were successfully obtained in 692 patients at base-line.Carotid IMT was measured in B-mode, using Philips ATL HDI 5000  with a 4–7 MHz linear transducer . Three cBlood samples were drawn in the morning following a 10 h over-night fast. The Swedish Mono-S HPLC standard was used for HbA1c analyses , but thet test, Chi square test or, where appropriate, Fisher's exact test. With the use of Cox regression models, the associations between the time to a first endpoint event and the presence of diastolic or systolic orthostatic hypertension or hypotension, were calculated as the hazard ratio (HR) for each group with a corresponding 95 % confidence interval (C.I.). Crude HRs were first calculated, and if they were significant, adjusted HRs were then calculated by using multivariate Cox regression models which adjusted for traditional cardiovascular risk factors. The first multivariate model adjusted for age, sex and sitting systolic blood pressure, and the second multivariate model adjusted additionally for smoking status, low density lipoprotein (LDL) cholesterol, body mass index and use of any antihypertensive medication. If the crude hazard ratios were not statistically significant, no further adjustments were made. Statistical significance was defined as P < 0.05. Since the purpose of the study was to present adjusted HRs, and not to screen for independent predictors, no adjustments for multiple testing were performed.For the statistical analyses, SPSS software  was used. In the main comparisons, the reference group was defined as patients who had a normal systolic and diastolic orthostatic blood pressure response. Differences of base-line characteristics were tested for statistical significance with two-sided independent All participants gave written informed consent. The merging of study data with other registries was approved by the National Board of Health and Welfare and by the Swedish Data Inspection Board. The study was approved by the Regional Ethical Review Board in Linköping, Sweden. The study protocol followed the principles expressed in the Declaration of Helsinki.The study population consisted of 257 women (34.3 %) and 492 men. The majority (88.5 %) were born in Sweden. The most common anti-diabetic treatment strategy was oral anti-diabetics (OAD) and/or non-insulin injectables (NNI) which were used by 40.9 percent of the participants, followed by life-style advice only (28.2 %), combined use of insulin with OAD/NNI 18.0 %) and insulin only (13.0 %). There were 462 participants (61.7 %) who reported a previous diagnosis of hypertension, 67 participants (8.9 %) who reported having had a myocardial infarction and 18 participants (2.4 %) who reported having had a stroke. Background characteristics are presented according to the orthostatic blood pressure reaction  with the 534 patients who had a normal systolic and diastolic orthostatic blood pressure response, systolic orthostatic hypertension was not significantly associated with the risk of the combined end-point . Similar results were obtained when the 45 patients with systolic orthostatic hypertension were compared with the 704 patients without systolic orthostatic hypertension  or with the 680 patients who had a normal systolic blood pressure response . Patients with systolic blood pressure rise ≥20 mmHg had significantly (P = 0.001) higher PWV than patients with a normal orthostatic blood pressure response, but similar IMT  with the 534 patients who had a normal systolic and diastolic orthostatic blood pressure response, systolic orthostatic hypotension was not significantly associated with the risk of the combined end-point . Similar results were obtained when the 24 patients with systolic orthostatic hypotension were compared with the 725 patients without systolic orthostatic hypotension  or with the 680 patients who had a normal systolic blood pressure response . Patients with systolic blood pressure fall ≥ 20 mmHg had non-significantly higher PWV and IMT compared with patients with a normal orthostatic blood pressure response  had a significantly lower risk of experiencing the combined end-point compared with the 534 patients who had a normal systolic and diastolic orthostatic blood pressure reaction . Diastolic orthostatic hypertension remained significantly associated with a decreased risk for cardiovascular events following adjustment for age, sex and sitting systolic blood pressure  as well as following additional adjustment for smoking status, LDL cholesterol, body mass index and use of any antihypertensive medication . The results of the fully adjusted model are presented in Table Patients with diastolic orthostatic hypertension (n = 31) were compared with the 534 patients who had a normal systolic and diastolic blood pressure response . The same non-significant trend was observed when patients with diastolic orthostatic hypotension were compared with the 718 patients without diastolic orthostatic hypotension  or with the 578 patients who had a normal diastolic blood pressure response . Patients with diastolic orthostatic hypotension had significantly (P = 0.013) higher PWV and significantly (P = 0.010) higher IMT than patients with a normal orthostatic blood pressure response (Table There was a non-significant trend towards increased risk for the combined end-point when patients with diastolic orthostatic hypotension (n = 172) were grouped together and compared with the 534 patients with a normal orthostatic blood pressure response, the presence of any hypertensive orthostatic blood pressure response was associated with a decreased risk for the composite end-point of borderline statistical significance  and with significantly higher PWV  but similar IMT . When patients who had either systolic or diastolic orthostatic hypotension or both (n = 49) were compared with the 534 patients with a normal orthostatic blood pressure response, there was no significant association with the presence of any hypotensive orthostatic blood pressure response and the composite end-point  but significantly higher values were found for both PWV  and IMT .When patients who had either systolic or diastolic orthostatic hypertension or both  for systolic orthostatic hypertension, 1.119  for systolic orthostatic hypotension, 0.285  for diastolic orthostatic hypertension, and 1.728  for diastolic orthostatic hypotension. For patients with either systolic or diastolic orthostatic hypertension or both, the hazard ratio was 0.394  and for patients with either systolic or diastolic orthostatic hypotension or both, the hazard ratio was 1.342 .Since previous cardiovascular disease is a risk factor for recurrent events, we performed a sensitivity analysis, in which 86 patients were excluded due to reporting either previous myocardial infarction or previous stroke, or due to missing baseline data concerning these variables. When compared with patients with a normal orthostatic blood pressure response, the hazard ratio for the combined end-point was 1.010 (95 % C.I. 0.312–3.272, The principal finding of this prospective observational cohort study was that diastolic orthostatic hypertension was found in nearly one in five patients with type 2 diabetes, and that this condition was associated with a decreased risk for incident cardiovascular events, independently of classical cardiovascular risk factors.The prevalence of orthostatic hypertension in our cohort was similar to previously reported data from patients with long term type 1 diabetes  and middConsidering previously reported data from patients with diabetes mellitus , 2, we fSince diastolic blood pressure control is particularly important in patients with diabetes mellitus , our finEarly pathogenetic studies  on orthoIn the present study, we did not find a statistically significant increased risk in patients with orthostatic hypotension, regardless of whether diastolic or systolic diagnostic criteria were applied. This is in contrast to several previously published reports –12. ThisStrengths of our study include the community-based approach, in which patients were recruited from primary care with few exclusion criteria and with no patients lost to follow-up. In our opinion, the most important study limitation was that few patients fulfilled the criteria for diastolic or systolic orthostatic hypotension. Thus, the lack of statistically significant associations between orthostatic hypotension and the combined end-point may be attributable to a lack of statistical power. Furthermore, there were relatively few events, which precludes us from exploring possible gender differences, and from separately studying patients with or without antihypertensive medications. Larger studies that directly compare the predictive value of different orthostatic blood pressure reactions, as well as the impact of different antihypertensive drugs on orthostatic blood pressure reactions, should be encouraged in patients with type 2 diabetes. Finally, it should be noted that the orthostatic blood pressure response was diagnosed at one single occasion. Since the reproducibility of orthostatic blood pressure reactions has been shown to be poor , it is pDiastolic orthostatic hypertension was common in patients with type 2 diabetes, and was associated with a decreased cardiovascular risk, whereas diastolic orthostatic hypotension was associated with significantly increased degree of sub-clinical target organ damage. Evaluation of the orthostatic blood pressure reaction is easy to perform in everyday clinical praxis, and should be encouraged in patients with type 2 diabetes. We suggest that health care providers pay attention to the diastolic orthostatic blood pressure response, which was frequently abnormal in our cohort, and which may add independent prognostic information beyond traditional risk factors. Larger studies aiming at determining the optimal definitions of orthostatic blood pressure reactions, as well as the number of measurements required to confirm the diagnosis, seem warranted in patients with type 2 diabetes.


EFT was higher in female than in male patients  and higher in the obese female EH group (7.5 ± 2.6 mm) than in the control (6.4 ± 2.8 mm) or nonobese EH group (6.7 ± 2.8 mm) among women, whereas EFT did not vary among males . Multivariate logistic regression analysis demonstrated that the 24-hour mean BP variability was associated with SBP (p = 0.018) and EFT (p = 0.016) in female patients, but not in male patients. The relationships among circadian BP variability, obesity, and EFT were affected by gender in different manners. EFT may be a more valuable parameter in the evaluation of BP severity and obesity in women than in men.This study aimed to investigate the effects of gender on the association between epicardial fat thickness (EFT) and circadian blood pressure (BP) changes in patients with recently diagnosed essential hypertension (EH). A total of 441 patients with EH  and 83 control patients underwent 24-hour ambulatory BP monitoring and echocardiography. Obese EH patients had higher circadian BP profile with BP variability, wall thickness, and left ventricular mass than nonobese EH patients and controls (all  Obesity is a worldwide phenomenon, with an incidence increasing in parallel with obesity-associated diseases such as insulin resistance, type 2 diabetes mellitus, and hypertension . The comEpicardial adipose tissue is related to visceral fat, rather than total adiposity, and shares microcirculation with myocardial tissue and coronary vessels , 7. BecaThis cross-sectional observational single-center cohort study included patients who underwent 24 h ABPM and echocardiography between January 2008 and October 2013. Demographic characteristics recorded at the first visit included age, sex, height, weight, medication, smoking history, and other diseases. Blood was drawn for measurement of total serum cholesterol, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, blood glucose, creatinine, uric acid, and high sensitivity C-reactive protein (hs-CRP). Body mass index (BMI) was calculated as the ratio of dry weight in kilograms to height squared (in square meters). This study was approved by the Institutional Review Board. All patients were required to provide written informed consent to participate.2, as per the Korean Society for the Study of Obesity [A total of 441 consecutive patients, who underwent office BP measurements, 24-hour ABPM, and laboratory measurements for cardiovascular risk factors and echocardiography, were analyzed. Following the recommendations of the European Society of Hypertension , a normo Obesity . Other iThe patients with the following diseases were excluded from the study: secondary hypertension, significant liver disease, neurologic disorder, malignant disease, valvular heart disease, heart failure, and history of acute coronary syndrome, myocardial infarction, coronary revascularization procedure, carotid revascularization procedure, ischemic leg ulcer, peripheral revascularization, or amputation. Because the presence of type 2 DM is known to be associated with increased EFT regardless of obesity , 7, we aEASY X 800 (R/L), JAWON Medical, Seoul, Korea). Measurements were taken after patients had rested for 10 min in a sitting position, with the arm comfortably placed at the heart level. Two measurements were taken at 5 min intervals. Each set of two measurements was averaged to give the office systolic and diastolic BP. ABPM was performed on each patient's nondominant arm using an automatically oscillometric device  on a normal working day. All subjects were instructed to rest or sleep between 10:00 pm and 7:00 am (nighttime) and to continue their usual activities between 7:00 am and 10:00 pm (daytime). The accuracy of the device was checked against the standard auscultatory method to ensure that the difference in BP measurements between methods did not exceed 5 mmHg. The device was set to obtain BP readings at 20 min intervals during the day (7:00 am–10:00 pm) and at 40 min intervals during the night (10:00 pm–7:00 am). Only 24-hour recordings including more than 80% of successful recordings were accepted as valid. Each ABPM dataset was first automatically scanned to remove artifactual readings according to preselected editing criteria. Data were edited by omitting all readings of zero, all heart rate readings <20 or >200, diastolic BP readings >150 and <40 mmHg, systolic BP readings >240 and <70 mmHg, and all readings where the difference between systolic and diastolic BPs was less than 10 mmHg. The following ABPM parameters were evaluated: average ambulatory 24-hour systolic and diastolic BP levels, average ambulatory daytime systolic and diastolic BP levels, average ambulatory nighttime systolic and diastolic BP levels, and mean ambulatory 24-hour, daytime, and nighttime BPs. Additionally, for both SBP and DBP, the magnitude of the nocturnal decline in BP  was calculated as follows: daytime average BP minus nighttime average; the percentage change in BP from day to night (% day–night BP) was calculated as (daytime BP − nighttime BP) ×100/daytime BP. With this latter data, a normal dipper pattern was diagnosed when the reduction in the average SBP and DBP during the nighttime was ≥10% of the average daytime values. The nocturnal BP status was also assessed and expressed as either nocturnal normotension or hypertension, with nocturnal hypertension defined as a nighttime BP of ≥120/70 mmHg.Office BP measurements were performed using an automated device  and strain echocardiography were performed on all subjects while lying in the left lateral decubitus position using a 3.5 MHz transducer , and the echocardiography examiners were blinded to patient information. Measurements of the thickness of interventricular septum and posterior wall, the diameter of the LV cavity, and the LV mass index (LVMI) were performed according to American Society of Echocardiography criteria . Pulsed Echocardiographic assessments of the EFT were measured perpendicularly from the free wall of the right ventricle at end-systole in three cardiac cycles according to the method previously described by Iacobellis et al.  Figure . Epicard t-test. Analysis of categorical data was carried out by Chi-square test. Pearson correlations analysis was performed to determine factors that potentially influenced BP and HR variability. Multivariate logistic regression models for BP variability were built to determine which variables were independently associated with this status. A two-tailed p < 0.05 was considered to be statistically significant.Statistical analyses were performed with the commercially available computer program SPSS 18.0 for Windows . Values are expressed as mean ± standard deviation or as a percentage (%). The normality of data was tested using the Kolmogorov-Smirnov test. Parameter differences among the 3 groups were evaluated using the one-way ANOVA test for normally distributed variables and the Kruskal-Wallis test for non-normally distributed variables. Values are expressed as means (standard deviation) if numerical variables or as the number of subjects and their percentages (%), if categorical. Continuous variables were compared using Student'sA total of 441 patients with EH  and 83 normotensive normal weight patients  were analyzed, and their clinical features and ambulatory blood pressure parameters according to gender are given in  p's < 0.05). Moreover, the proportion of patients with a nondipping pattern was the highest among the hypertensive obese patients. Although there were no significant differences in HR variability among the groups, hypertensive obese patients had higher daytime and 24-hour mean HR and male hypertensive obese patients also had higher nighttime HR than control patients . Although total cholesterol levels were higher in hypertensive obese patients of both genders than in the controls, male hypertensive obese patients had higher triglycerides and female hypertensive obese patients had lower HDL cholesterol than controls . Although there was no significant difference in systolic function, hypertensive patients showed significantly increased wall thickness and enlarged left atrial diameter, which were more prominent among hypertensive obese patients, without gender difference (Tables p < 0.001). Among women, EFT was highest in the obese EH group (7.5 ± 2.6 mm) whereas that of the control was 6.4 ± 2.8 mm and that of the nonobese EH group was 6.7 ± 2.8 mm; however, EFT did not vary significantly among males .Circadian BP profile and BP variability assessed by 24-hour mean BPs variation were increased in hypertensive patients, especially in hypertensive obese patients, without gender difference  and a greater daytime BP variation  than male subjects; males had higher 24-hour mean BP  and HR variability  than female subjects , 24-hour mean BP , day systolic BP , day systolic BP variation , night systolic BP , night systolic BP variation , night diastolic BP , and night diastolic BP variation . However, no correlation was shown between EFT/BMI and 24-hour ABPM parameters in male. Multivariate logistic regression analysis demonstrated that the 24-hour mean BP variability was associated with SBP  and EFT  in female patients, but not in male ones (p = 0.001)  .The most relevant information obtained from this study is that relationships among EFT, obesity, and circadian BP variability are affected by gender in different manners. Although circadian BP profile and BP variability were increased in hypertensive obese patients without gender differences, female patients had significantly higher EFT and greater daytime BP variability than male subjects. BP variability was associated with SBP and EFT only in female patients; therefore, EFT may be a more valuable parameter in the evaluation of BP severity and obesity in women than in men.The severity of hypertension increased significantly with the degree of obesity. BMI is known to be associated with the severity of ambulatory hypertension and increased daytime BP . In the p = 0.016). Still yet, there is no consensus in the literature on the impact of gender on the amount of epicardial fat. Iacobellis et al. showed bigger size of EFT in males than in females [Regarding gender differences, obese females showed a higher tendency towards BP variability than obese males. One interesting finding was that females showed a significant relationship between increased EFT, obesity, and BP variability, but this was not the case in males. This significance still remained after multivariate regression analysis ( females , and our females  showed l females , 26 and  females , 27. It  females  and that females . Thus, o females . Insulin females . Increas females . Several females , 31, and females . In our  females .This study has some potential shortcomings. Although our patient sample seems sufficiently large compared to other studies in the literature, in this cross-sectional study we observed predictive factors and outcome variables simultaneously and had no follow-up data. Thus, it was difficult to establish any causal or temporal relationship. Moreover, although we suggested that the hyperinsulinemia would be the possible main cause of elevated nighttime HR levels, we did not measure the plasma insulin levels. Because both pre- and postmenopausal women were included in the study, we cannot assume the impact of estrogen on epicardial fat. Finally, all participants were Korean, and we thus cannot generalize our results to populations of other ethnic groups. In conclusion, the relationship among EFT, obesity, and circadian BP variability was affected by gender in different manners. EFT may be a more valuable parameter in the evaluation of BP severity and obesity in women than in men.