Blood Pressure-lowering Drugs Research Articles

Medication adherence in patients with apparent resistant hypertension: findings from the SYMPATHY trial.

Hypertension is only controlled in approximately 35% of the patients, which could be partially due to nonadherence. Recently, bioanalytical assessment of adherence to blood pressure (BP) lowering drugs has gaining interest. Our aim was to explore possible determinants of nonadherence in treatment resistant hypertension, assessed by objective screening for antihypertensive agents in serum. The secondary aim was to study the effect of adherence on the change in BP. This project was a substudy of SYMPATHY; an open-label randomized-controlled trial to assess the effect of renal denervation on BP 6months after treatment compared to usual care in patients with resistant hypertension. Stored serum samples were screened for antihypertensive agents to assess adherence at baseline and 6months after intervention, using liquid chromatography-tandem mass spectrometry. Office and 24-h BP were measured on the same day as blood was sampled. Patients and physicians were unaware of adherence measurements. Ninety-eight baseline and 83 6-month samples were available for analysis. Sixty-eight percent [95% confidence interval (CI) 59-78%] of the patients was nonadherent (n=67). For every onw pill more prescribed, 0.785 [95%CI 0.529-0.891] prescribed pill was less detected in blood. A decrease of one pill in adherence between baseline and 6months was associated with a significant rise in office systolic BP of 4 (95%CI 0.230-8.932) mmHg. Objective measurement of BP lowering drugs in serum, as a tool to assess adherence, showed that nonadherence was very common in patients with apparent resistant hypertension. Furthermore, the assessment results were related to (changes in) blood pressure. Our findings provide direct and objective methodology to help the physician to understand and to improve the condition of apparent resistant hypertension.

ANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE DETERMINATION OF OMEPRAZOLE AND ASPIRIN USING REVERSE PHASE HPLC METHOD IN BULK AND DOSAGE FORM

Objectives: A new simple, accurate, precise and reproducible RP-HPLC method has been developed for the simultaneous estimation of Aspirin and Omeprazole in bulk and pharmaceutical dosage form using C18 column (Agilent, 250 x 4.6 mm, 5μm) in isocratic mode. Methods: The mobile phase consisted of Methanol and 0.1 M Di-potassium Phosphate buffer (pH 3) in the ratio of 60:40 v/v. The detection was carried out at 256 nm. The method was linear over the concentration range for Omeprazole 50-250 μg/ml and for Aspirin 10-50μg/ml. Results: The recoveries of Omeprazole and Aspirin were found to be 100.07 and 100.06% respectively. The validation of method was carried out utilizing ICH-guidelines. The described HPLC method was successfully employed for the analysis of pharmaceutical formulations containing combined dosage form. Conclusion: Study concludes that the proposed method is accurate, precise, rapid and selective has advantage of simplicity and convenience for the separation and quantitation of ASP and OMP in the combination which can be used for the assay of their dosage form. Peer Review History: Received 22 August; Revised 28 August; Accepted 5 September, Available online 15 September 2017 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.0/10 Average Peer review marks at publication stage: 7.5/10 Reviewer(s) detail: Dr. Showkat Ahmad Bhawani, UNIMAS Sarawak, Malaysia, sabhawani@gmail.com Dr. Maya Shaaban Eissa Hussein, Egyptian Russian University, Egypt, maya-shaaban@hotmail.com Similar Articles: VALIDATION OF HPLC AND UV VISIBLE METHODS FOR FEW SELECTED BLOOD PRESSURE LOWERING DRUGS AND THEIR FORMULATIONS

Abstract 019: Effect of CPAP on Blood Pressure and Central Sympathetic Outflow in Diabetic Patients with OSA, Resistant HTN, and CKD

Introduction: Central sympathetic hyperactivity as assessed by muscle sympathetic nerve activity recordings is thought to play a crucial role in the development and maintenance of hypertension (HTN) in patients with obstructive sleep apnea (OSA). Decreases in daytime and nocturnal blood pressure (BP) in response to treatment with continuous positive airway pressure (CPAP) are paralleled by decreases in muscle sympathetic nerve activity (MSNA). Patients with chronic kidney disease (CKD) have high MSNA. Bilateral nephrectomy, but not renal transplantation normalizes MSNA indicating central sympathoexcitatory effects by renal afferents. The objective of this study was to assess to what extent is HTN driven by central sympathetic hyperactivity in patients with diabetic CKD, OSA, and resistant HTN. Thirteen patients (age 62.2±7.4 years) with diabetic CKD, resistant HTN defined as SBP on 24-hr ABPM above 135 mmHg while on 3 or more BP lowering drugs (including diuretic) with OSA, were randomized to therapeutic CPAP or non-therapeutic CPAP for one months. 24-hr ABPM, plasma catecholamines, aldosterone, and renin, and MSNA were assessed before and 1 months after randomization. Our results show (Table) that in contrast to sham CPAP, therapeutic CPAP decreased daytime and nighttime BP. In contrast, neither therapeutic nor sham CPAP caused any changes in MSNA and plasma catecholamines. In conclusion, decreases in BP in response to CPAP in patients with in diabetic CKD, despite maintained high MSNA, indicate other mechanism contributing to HTN in these patients as well as other central sympathoexcitatory pathways activated.

Availability and affordability of blood pressure-lowering medicines and the effect on blood pressure control in high-income, middle-income, and low-income countries: an analysis of the PURE study data

Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development. We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level. The availability of two or more classes of blood pressure-lowering drugs was lower in low-income and middle-income countries (except for India) than in high-income countries. The proportion of communities with four drug classes available was 94% in high-income countries (108 of 115 communities), 76% in India (68 of 90), 71% in upper-middle-income countries (90 of 126), 47% in lower-middle-income countries (107 of 227), and 13% in low-income countries (nine of 68). The proportion of households unable to afford two blood pressure-lowering medicines was 31% in low-income countries (1069 of 3479 households), 9% in middle-income countries (5602 of 65 471), and less than 1% in high-income countries (44 of 10 880). Participants with known hypertension in communities that had all four drug classes available were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio [OR] 2·23, 95% CI 1·59-3·12); p<0·0001), combination therapy (1·53, 1·13-2·07; p=0·054), and have their blood pressure controlled (2·06, 1·69-2·50; p<0·0001) than were those in communities where blood pressure-lowering medicines were not available. Participants with known hypertension from households able to afford four blood pressure-lowering drug classes were more likely to use at least one blood pressure-lowering medicine (adjusted OR 1·42, 95% CI 1·25-1·62; p<0·0001), combination therapy (1·26, 1·08-1·47; p=0·0038), and have their blood pressure controlled (1·13, 1·00-1·28; p=0·0562) than were those unable to afford the medicines. A large proportion of communities in low-income and middle-income countries do not have access to more than one blood pressure-lowering medicine and, when available, they are often not affordable. These factors are associated with poor blood pressure control. Ensuring access to affordable blood pressure-lowering medicines is essential for control of hypertension in low-income and middle-income countries. Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research Strategy for Patient Oriented Research through the Ontario SPOR Support Unit, the Ontario Ministry of Health and Long-Term Care, pharmaceutical companies (with major contributions from AstraZeneca [Canada], Sanofi Aventis [France and Canada], Boehringer Ingelheim [Germany amd Canada], Servier, and GlaxoSmithKline), Novartis and King Pharma, and national or local organisations in participating countries.

A cost-benefit analysis of a National Hypertension Treatment Program in Bangladesh

IntroductionHypertension is one of the most common, yet manageable, risks for life-threatening events like stroke and myocardial infarction in the world. Bangladesh adults experience high rates of hypertension, with one in three women and one in five men meeting the condition's clinical definition. In the midst of an epidemiological transition, Bangladesh has the opportunity to slow the growth of hypertension prevalence through increased coverage of anti-hypertensive drugs for high-risk patients. MethodsUsing economic cost-benefit analysis and a societal perspective, we model the return on investment of providing blood-pressure lowering drugs to 60% of hypertensive adults by 2021 and 2030. We stratify the projections on both gender and income quintile. ResultsIf the government of Bangladesh is proactive about hypertension management now, they could see a 12.7: 1 annual return on investment by 2021 and an 8.6: 1 annual return on investment by 2030. The return on investment is higher for providing medication for women than for men in both time horizons.Conclusion: Bangladesh has a unique opportunity to address hypertension now in order to prevent thousands of premature deaths and to accrue substantial net economic benefits within 6years.

A new look at risk patterns related to coronary heart disease incidence using survival tree analysis: 12 Years Longitudinal Study

We identified risk patterns associated with incident coronary heart disease (CHD) using survival tree, and compared performance of survival tree versus Cox proportional hazards (Cox PH) in a cohort of Iranian adults. Data on 8,279 participants (3,741 men) aged ≥30 yr were used to analysis. Survival trees identified seven subgroups with different risk patterns using four [(age, non-HDL-C, fasting plasma glucose (FPG) and family history of diabetes] and five [(age, systolic blood pressure (SBP), non-HDL-C, FPG and family history of CVD] predictors in women and men, respectively. Additional risk factors were identified by Cox models which included: family history of CVD and waist circumference (in both genders); hip circumference, former smoking and using aspirin among men; diastolic blood pressure and lipid lowering drug among women. Survival trees and multivariate Cox models yielded comparable performance, as measured by integrated Brier score (IBS) and Harrell’s C-index on validation datasets; however, survival trees produced more parsimonious models with a minimum number of well recognized risk factors of CHD incidence, and identified important interactions between these factors which have important implications for intervention programs and improve clinical decision making.

Impact of Medication Adherence on the Effect of Renal Denervation: The SYMPATHY Trial.

URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850901.

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review

Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

Hypertension Management in Brazil: Usual Practice in Primary Care-A Meta-Analysis.

Knowing the usual clinical practice is relevant for evaluations in health care and economic policies of management of hypertension. This study aimed to describe the usual management of hypertension in the Brazilian primary healthcare system through a systematic review and meta-analysis. The search of population-based studies conducted in Brazil was undertaken using PubMed, EMBASE, and Brazilian databases. Eligible studies were those conducted in adults with hypertension (blood pressure (BP) ≥ 140/90 mmHg or using BP lowering drugs). Three datasets' data were analyzed: SESI study (in Brazilian workers); HIPERDIA (Brazilian Registration and Monitoring of Hypertensive and Diabetic Patients Program); and a population-based study. Meta-analysis has been performed using the fixed and random effect models. A total of 11 studies or data sets were included in the systematic review. Hypertensive individuals had, on average, 2.6 medical visits annually and 18.2% were on diuretics (n = 811 hypertensive patients) and 16.2% on ACE inhibitors (n = 1768 hypertensive patients). BP control rate ranged from 43.7 to 67.5%; 35.5% had measured total cholesterol and 36.5% determined fasting plasma glucose in the previous 12 months. Thiazide diuretics and ACE inhibitors were the most used BP lowering medications as single drugs, but the control rate of hypertension is insufficient.

Screening for elevated albuminuria and subsequently hypertension identifies subjects in which treatment may be warranted to prevent renal function decline.

We investigated whether initial population screening for elevated albuminuria with subsequent screening for hypertension in case albuminuria is elevated may be of help to identify subjects at risk for accelerated decline in kidney function. We included subjects who participate in the PREVEND observational, general population-based cohort study and had two or more glomerular filtration rate (eGFR) measurements available during follow-up. Elevated albuminuria was defined as an albumin concentration ≥20 mg/L in a first morning urine sample confirmed by an albumin excretion ≥30 mg/day in two 24-h urines. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg or use of blood pressure-lowering drugs. eGFR was estimated with the CKD-EPI creatinine-cystatin C equation. Overall, 6471 subjects were included with a median of 4 [95% confidence interval (CI) 2-5] eGFR measurements during a follow-up of 11.3 (95% CI 4.0-13.7) years. Decline in eGFR was greater in the subgroups with elevated albuminuria. This held true, not only in subjects with known hypertension (-1.84 ± 2.27 versus -1.16 ± 1.45 mL/min/1.73 m 2 per year, P < 0.05), but also in subjects with newly diagnosed hypertension (-1.59 ± 1.55 versus -1.14 ± 1.38 mL/min/1.73 m 2 per year, P < 0.05) and in subjects with normal blood pressure (-1.18 ± 1.85 versus -0.81 ± 1.02 mL/min/1.73 m 2 per year in subjects, P < 0.05). This effect was most pronounced in the population ≥55 years of age and male subjects. In addition, subjects with elevated albuminuria had higher blood pressure than subjects with normoalbuminuria, and in subjects with elevated albuminuria as yet undiagnosed hypertension was twice as prevalent as diagnosed hypertension. Initial screening for elevated albuminuria followed by screening for hypertension may help to detect subjects with increased risk for a steeper decline in kidney function.

Development and validation of prescribing quality indicators for patients with type 2 diabetes.

Quality indicators are used to measure whether healthcare professionals act according to guidelines, but few indicators focus on the quality of pharmacotherapy for diabetes. The aim of this study was to develop and validate a set of prescribing quality indicators (PQIs) for type 2 diabetes in primary care, and to apply this set in practice. To take into account the stepwise treatment of chronic disease, clinical action indicators were specifically considered. Potential PQIs were derived from clinical practice guidelines and evaluated using the RAND/UCLA Appropriateness Method, a modified Delphi panel. Thereafter, the feasibility of calculating the PQIs was tested in two large Dutch primary care databases including >80000 diabetes patients in 2012. 32 PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on vaccination, medication safety and adherence were assessed by ten experts. After the Delphi panel, the final list of twenty PQIs was tested for feasibility. All PQIs definitions were feasible for measuring the quality of medication treatment using these databases. Indicator scores ranged from 18.8% to 90.8% for PQIs focusing on current medication use, clinical action and medication choice, and from 2.1% to 37.2% for PQIs focusing on medication safety. Twenty PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on medication safety in type 2 diabetes were developed, considered valid and operationally feasible. Results showed room for improvement, especially in initiation and intensification of treatment as measured with clinical action indicators.

Early vascular ageing as a new model to understand hypertension and arterial disease

Hypertension is a major cardiovascular risk factor and can be treated. The cardiovascular risk associated with hypertension, however, cannot be fully reversed by treatment with blood pressure-lowering drugs. One reason could be that not all risk factors are addressed at the same time, but another reason could well be that structural changes and remodelling of the arterial wall are not diminished nor normalized. One component that has attracted considerable research efforts in recent years is arterial stiffness, primarily involving the arteria media (elastin, collagen), but also the arterial intima and adventitia. Arterial stiffness in large elastic arteries can be measured by aortic pulse wave velocity from the carotid artery to the femoral artery and is considered to be both a cause and a consequence of hypertension. The treatment of arterial stiffness involves traditional antihypertensive drugs such as renin–angiotensin blocking agents, but new experimental drugs are under development such as the angiotensin-II agonist compound 21 currently being tested in humans.

Abstract 11603: Structural Insights Into C-terminus and N-terminus of a Designer cGMP Activating ANP-Based Antihypertensive Peptide: ZD100

Introduction: As importantly underscored by the SPRINT Trial, innovative blood pressure (BP) lowering and multiorgan protective drugs are needed for treating hypertension (HTN). We engineered a Mayo Clinic designer atrial natriuretic peptide (ANP)-based drug, ZD100, which possesses a unique 12 amino acid (AA) carboxy-terminus (CT) extension while maintaining the N-terminus (NT) of ANP. ZD100 is more potent than ANP in reducing BP, inducing natriuresis and inhibiting aldosterone via pGC-A and its second messenger cGMP. To date, the in vivo actions of ZD100 in a model of essential HTN are undefined. Further, in attempt to enhance and/or minimize pGC-A activation, the importance of specific AAs in the CT and NT of ZD100 is unknown and is critical to define. Hypothesis: We hypothesize that ZD100 is a potent anti-HTN drug activating pGC-A/cGMP system and that specific AA variations in the CT and/or NT of ZD100 will modify the ability of activating pGC-A. Methods: Spontaneously hypertensive rats (SHRs) received intravenous (IV) ZD100 or vehicle and BP, plasma and urinary cGMP and the natriuretic effects were determined. We then engineered 15 strategic ZD100 variants (Vs) consisting of mutated peptides in the CT or NT or both. We stimulated HEK293 cells overexpressing pGC-A with ZD100 and the 15 Vs (10-8 M) and measured intracellular cGMP generation. Results: In SHRs, acute IV ZD100 reduced BP, increased plasma and urinary cGMP generation and induced natriuresis demonstrating efficacy in HTN. In vitro, we found two more potent pGC-A activators (+100% cGMP activation) only among the CT-only mutated ZD100 Vs. Importantly, key mutations of either the CT or NT resulted in 6 loss-of-function Vs identifying importance of peptide-receptor dependency. Conclusions: We demonstrate for the first time in a genetic model of HTN that ZD100 reduces BP, activates systemic and renal pGC-A/cGMP and induces natriuresis. Enhanced or reduced pGC-A activation with targeted AA mutations in the CT and NT of ZD100 provides key structure function insights into ZD100 which may lead to next generation ZD100 therapeutic peptides. These findings support ZD100 as a novel peptide therapeutic strategy for HTN and will help guide the selection of best-in-class ZD100 analogues.

Mesoporous silica nanoparticles as a new carrier methodology in the controlled release of the active components in a polypill

Polypill is a medication designed for preventing heart attacks through a combination of drugs. Current formulations contain blood pressure-lowering drugs and others, such statins or acetylsalicylic acid. These drugs exhibit different physical chemical features, and consequently different release kinetics. Therefore, the concentration in plasma of some of them after the release process can be out of the therapeutic range. This paper investigates a new methodology for the control dosage of a polypill recently reported containing hydrochlorothiazide, amlodipine, losartan and simvastatin in a 12.5/2.5/25/40 weight ratio. The procedure is based on mesoporous silica nanoparticles (MSN) with MCM-41 structure (MSN-41) used as carrier, aimed to control release of the four drugs included in the polypill. In vitro release data were obtained by HPLC and the curves adjusted with a kinetic model. To explain the release results, a molecular model was built to determine the drug-matrix interactions, and quantum mechanical calculations were performed to obtain the electrostatic properties of each drug. Amlodipine, losartan and simvastatin were released from the polypill-MSN-41 system in a controlled way. This would be a favourable behavior when used clinically because avoid too quick pressure decrease. However, the diuretic hydrochlorothiazide was quickly released from our system in the first minutes, as is needed in hypertensive urgencies. In addition, an increase in the stability of amlodipine and hydrochlorothiazide occurred in the polypill-MSN-41 system. Therefore, the new way of polypill dosage proposed can result in a safer and effective treatment.

Role of Patient and Practice Characteristics in Variance of Treatment Quality in Type 2 Diabetes between General Practices.

BackgroundAccounting for justifiable variance is important for fair comparisons of treatment quality. The variance between general practices in treatment quality of type 2 diabetes (T2DM) patients may be attributed to the underlying patient population and practice characteristics. The objective of this study is to describe the between practice differences in treatment, and identify patient and practice level characteristics that may explain these differences.MethodsThe data of 24,607 T2DM patients from 183 general practices in the Netherlands were used. Treatment variance was assessed in a cross-sectional manner for: glucose-lowering drugs/metformin, lipid-lowering drugs/statins, blood pressure-lowering drugs/ACE-inhibitor or ARB. Patient characteristics tested were age, gender, diabetes duration, comorbidity, comedication. Practice characteristics were number of T2DM patients, practice type, diabetes assistant available. Multilevel logistic regression was used to examine the between practice variance in treatment and the effect of characteristics on this variance.ResultsTreatment rates varied considerably between practices (IQR 9.5–13.9). The variance at practice level was 7.5% for glucose-lowering drugs, 3.6% for metformin, 3.1% for lipid-lowering drugs, 10.3% for statins, 8.6% for blood pressure-lowering drugs, and 3.9% for ACE-inhibitor/ARB. Patient and practice characteristics explained 19.0%, 7.5%, 20%, 6%, 9.9%, and 13.4% of the variance respectively. Age, multiple chronic drugs, and ≥3 glucose-lowering drugs were the most relevant patient characteristics. Number of T2DM patients per practice was the most relevant practice characteristic.DiscussionConsiderable differences exist between practices in treatment rates. Patients’ age was identified as characteristic that may account for justifiable differences in especially lipid-lowering treatment. Other patient or practice characteristics either do not explain or do not justify the differences.

Cholesterol- and blood-pressure-lowering drug use for secondary cardiovascular prevention in 2004-2013 Europe.

Background Suboptimal use of cardiovascular prevention medications has been reported. We report recent trends in secondary cardiovascular disease prevention drug use in Europe. Design We used the 2004-2013 data from the Survey of Health, Ageing and Retirement in Europe (SHARE), a large longitudinal cohort study in middle-aged and elderly Europeans. Methods Cross-sectional and panel data logistic regression models were used to study trends in cholesterol- and blood pressure-lowering drug use and effects of participant characteristics on the likelihood of drug use among participants with histoty of cardiovascular disease in SHARE. Results In SHARE 21,388 participants reported history of cardiovascular disease and provided data on cholesterol- and blood pressure-lowering drug use. At initial report, 40% and 60% of them used cholesterol- or blood pressure-lowering drugs, respectively. Increasing cross-sectional time trends were observed for both medication classes (odds ratios of use in 2013 vs. 2004, 1.6 (95% confidence interval 1.4-1.7) and 1.5 (1.4-1.6), respectively). However, among participants with multiple observations, the use of both classes declined over time (2013 vs. 2004 odds ratio 0.63 (0.51-0.77) and 0.68 (0.55-0.84), respectively; both trend p < 0.001), and with increasing duration since last cardiovascular event (odds ratio 0.74 (0.60-0.91), trend p = 0.01 and odds ratio 0.82 (0.66-1.03), trend p = 0.06, respectively for durations of nine years or more versus less than one year). Among people with history of cardiovascular disease, those obese, retired or with hypercholesterolaemia, hypertension, worse self-perceived health, and, in the case of lipid-lowering medication, with diabetes, were more likely to use these medications. Conclusions Despite moderately increasing cross-sectional time trends, the use of secondary cardiovascular disease prevention drugs remains low in Europe with substantial discontinuation over time and with increasing duration from an acute cardiovascular event.

OS 06-09 THE SYNERGISTIC ASSOCIATION BETWEEN VITAMIN D AND VITAMIN K WITH INCIDENT HYPERTENSION

OBJECTIVE: Vitamin D plays an important role in calcium homeostasis. The role of vitamin D in bone and cardiovascular health has mainly been studied in isolation and the synergistic effect of vitamin D and vitamin K is largely unknown. We assessed whether serum 25-hydroxyvitamin D [25(OH)D] levels and dephosphorylated, uncarboxylated matrix Gla protein (dp-unMGP) levels -an established marker of vitamin K status- are associated with incident hypertension among older adults in the Netherlands. DESIGN AND METHOD: We used data from the Longitudinal Aging Study Amsterdam (LASA), a population-based, prospective cohort with baseline measurements obtained between 2002 and 2003 and 3 follow-up exams. We studied 257 men and women, aged 55 to 65 years free of prevalent cardiovascular disease, hypertension and use of anti-hypertensive medication with follow-up data. We measured serum 25(OH)D and dp-ucMGP from previously frozen baseline samples. We used Cox-regression analyses to estimate hazard ratios and 95% confidence intervals for 25(OH)D and dp-ucMGP categories with incident hypertension through 2012 (blood pressure ≥140/90 mmHg or initiation of blood pressure-lowering drugs). RESULTS: During a median follow-up of 6.1 years, 52% of the cohort (n = 133) developed hypertension. Mean ± SD serum concentration of 25(OH)D was 58.9 ± 22.3 nmol/L and median dp-ucMGP was 310 (IQR: 209-425) nmol/L. Compared with the category of 25(OH)D ≥50nmol/L and dp-ucMGP < 310 nmol/L, the category 25(OH)D < 50 nmol/L and dp-ucMGP ≥310 was associated with a greater hazard ratio for incident hypertension: 1.72 (1.06, 2.81) adjusting for age, sex, body mass index, and type 2 diabetes. This hazard ratio was larger than for serum 25(OH)D < 50 nmol/L or dp-ucMGP≥310 nmol/L: HR 1.08 (0.67, 1.72) and 1.43 (0.85, 2.41), respectively. CONCLUSIONS: Serum 25(OH)D and dp-ucMGP are synergistically associated with a greater risk of developing hypertension. Randomized controlled trials should investigate whether supplementation of both vitamin D and vitamin K can lower blood pressure and hypertension risk.

Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model. Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent. Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS.

EMPA-REG and Other Cardiovascular Outcome Trials of Glucose-lowering Agents: Implications for Future Treatment Strategies in Type 2 Diabetes Mellitus

During the last decade, the armamentarium for glucose-lowering drugs has increased enormously by the development of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors, allowing individualization of antidiabetic therapy for patients with type 2 diabetes (T2DM). Some combinations can now be used without an increased risk for severe hypoglycemia and weight gain. Following a request of the US Food and Drug Administration, many large cardiovascular (CV) outcome studies have been performed in patients with longstanding disease and established CV disease. In the majority of CV outcome studies, CV risk factors were well controlled and a high number of patients were already treated with ACE inhibitors/angiotensin receptor blockers, statins and antiplatelet drugs. Most studies with insulin glargine and newer glucose-lowering drugs (saxagliptin, alogliptin, sitagliptin, lixisenatide) demonstrated safety of newer glucose-lowering agents but did not show superiority in the CV outcomes compared with placebo. By contrast, in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study, CV death, all-cause mortality, and hospitalization for heart failure were significantly decreased when empagliflozin was added instead of placebo to therapy for patients with high CV risk and T2DM already well treated with statins, glucose-lowering drugs, and blood pressure–lowering drugs as well as antiplatelet agents. In addition, renal endpoints including endstage renal disease were also significantly reduced when empagliflozin was added instead of placebo. Interestingly, the reduction of these clinically relevant end points was observed after a few months, making antiatherogenic effects an unlikely cause. The fact that the incidence of myocardial infarction (MI) and stroke were not reduced is in line with the hypothesis that hemodynamic factors in particular have contributed to the impressive improvement of the prognosis. To reduce the CV burden of patients with T2DM, drugs influencing factors involved in atherogenesis (eg, insulin resistance, chronic inflammation, increase of HDL, prothrombotic state) are more promising. The recent IRIS (Insulin Resistance Intervention after Stroke) study documented a significant reduction in stroke and MI when pioglitazone instead of placebo was given to nondiabetic patients presenting with both stroke/transient ischemic attack and insulin resistance, confirming results from the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study in patients with T2DM. Based on these new data, we suggest that the addition of both empagliflozin and pioglitazone to metformin might be the relative best option to reduce the high CV morbidity and mortality of patients with T2DM and already established CV complications. The very recent announcement that the CV outcome study with liraglutide (LEADER) also demonstrated a significant reduction of the composite endpoint (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) gives new hope for further beneficial treatment options for T2DM patients with established CVD.

Dementia Rating Scale-2 normative data for middle-and older-aged Castilian speaking Spaniards

Objectives: The Dementia Rating Scale-2 (DRS-2) is frequently used as a dementia screening tool in clinical and research settings in Spain. The present study describes DRS-2 Total and subscale scores in community-dwelling Spaniards, aged 50–71, and provides normative data for its use in Castilian Spanish-speaking individuals. Methods: The sample consisted of 798 individuals who participated in an observational study on essential hypertension. Mean age was 62.8 years (SD = 5.4), mean education was 8.6 years (SD = 3.4) with 47.9% females. Almost all of them were receiving blood pressure-lowering drugs (93%) and most of them had fairly well-managed blood pressure control (M systolic/diastolic blood pressure = 142.3/77.0 ± 16.0/9.2 mm Hg). We applied a previously described method of data normalization from the Mayo’s Older Americans Normative Studies to obtain the Castilian Spanish DRS-2 norms. Results: Worse performance on Total and subscale scores was associated with older age (p < .05) and fewer years of education (p < .001). Women obtained lower raw Total scores than men (131.68 ± 7.2 vs. 133.10 ± 6.90, p < .005), but had fewer years of education (7.96 ± 3.33 vs. 9.17 ± 3.45, p < .001). This gender difference disappeared after correcting for age and years of education. Total and subscale scores are presented adjusted by age, and normative data are shown for Total scores adjusted by age and years of education. Conclusions: These norms are useful for studying cognitive status and cognitive decline in research and clinical settings in Castilian Spanish-speaking populations.