Stepwise treatment of uncontrolled HyperTensioN (Stepwise-HTN): Study design of a cluster randomised controlled trial in primary care.

BACKGROUND: Uncontrolled hypertension is a major health problem, and a key risk factor for cardiovascular disease. Most patients are detected and managed in primary care, but approximately 50% remains uncontrolled. Our aim is to assess whether a guided stepwise work-up management strategy for patients with uncontrolled hypertension in primary care would result in better blood pressure control in these patients compared to usual care. METHODS: A cluster randomised controlled trial aiming at randomizing 40 general practices to either "a protocolised stepwise work-up" or to "usual care". Uncontrolled hypertension is defined as an office blood pressure (BP) >140/90 mmHg while being prescribed three or more antihypertensive drugs simultaneously from different therapeutic classes for three or more months in an adequate dose. In the intervention arm, patients with uncontrolled hypertension will receive the stepwise approach, consisting of (i) excluding a white coat effect, (ii) re-evaluation of lifestyle, (iii) re-evaluation of drug adherence, (iv) optimalisation of antihypertensive treatment and (v) referral if the office BP is still >140/90 mmHg. The control group receives usual care in a regular program for cardiovascular risk management. The primary outcome is the absolute difference in the mean 24-h systolic BP between intervention and control arm after 8 months. Secondary outcomes include differences in the percentage of patients achieving a controlled BP, and time to reach a controlled BP. CONCLUSION: If stepwise treatment of uncontrolled hypertension is proven effective, the strategy could be implemented by blending the approach to the cardiovascular risk management already applied in general practice. Trial registration NTR7304, https://www.trialregister.nl/trial/7099.

[Critical doctors and cognitive bias]. / Kritische dokters en cognitieve bias.

A doctor with good critical thinking skills will intervene when required, but abstain from intervening wherever possible. He or she has the ability to apply resource stewardship, acknowledges the limitations of guidelines and is able to deviate from protocols when appropriate, with sound arguments for why this is in the patient's best interest. We believe that critical thinking is an important skill for any doctor, and that it will contribute to better patient-centred outcomes at lower societal costs and with greater job satisfaction among healthcare professionals. The current medical curriculum for medical students and doctors in specialty training in the Netherlands highlights several aspects (e.g. evidence-based medicine, shared decision making, cost awareness) that are required if the student is to become a critically thinking doctor. This focus should, however, be further emphasized, and should include knowledge of cognitive bias and the skills required for the critical thinking process. On the basis of three patient vignettes several forms of cognitive bias are described, along with bias-mitigation strategies.

[New guideline on hypertension sickens society]. / Nieuwe richtlijn hypertensie maakt mensen ziek.

The introduction in the USA of the new AHA Guideline on management of Hypertension has fuelled controversy on the optimal definition and treatment of hypertension. A more strict definition (130/80 mmHg) and the advice to treat the major part of the hypertensive population well below 140/90 mmHg is a recipe for medicalisation of society. Advocates of the guideline emphasise the growing body of evidence to support more aggressive treatment. This evidence however seems to focus merely on the reduction of risk on cardiovascular disease or death. It does not, however, take into account at what costs. These costs are not limited to actual cost-effectiveness of implementation of the new guideline but stretch far beyond to involve also the actual and societal costs of medicalisation.

Patient characteristics do not predict the individual response to antihypertensive medication: a cross-over trial.

Background: International guidelines on hypertension management do not agree on whether patient characteristics can be used for the first choice of treatment of uncomplicated essential hypertension. Objective: We wanted to identify predictive patient characteristics to the response of two different classes of antihypertensive drugs in patients with newly diagnosed hypertension in primary care. Methods: We conducted a prospective, open label, blinded endpoint cross-over trial in 120 patients with a new diagnosis of hypertension from 10 family practices. Patients received 4 weeks of 12.5 mgr hydrochlorothiazide once daily and 4 weeks of 80 mgr valsartan once daily, each followed by a 4-week washout. The sequence of drugs was randomized. Age, sex and menopausal state were recorded at run in and 24 h ambulatory blood pressure, office blood pressure, plasma renin concentration, NT-proBNP, potassium, estimated glomerular filtration rate, urinary albumin, body mass index and waist circumference at each regimen change. The difference in systolic blood pressure response between both study drugs, calculated from mean daytime ambulatory blood pressures, was the main outcome measure. Results: Ninety-eight patients (52% female; median age 53 years) were eligible for per-protocol-analysis. None of the studied variables were predictive for the difference in systolic blood pressure response. Individual systolic blood pressure responses ranged from an increase by 18 mmHg to a decrease of 39 mmHg. Conclusion: In a relevant group of primary care patients with newly diagnosed hypertension, we were unable to detect predictors of treatment response. This study rather supports the United States and European guidelines than the United Kingdom and Dutch guidelines on hypertension.

Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients.

The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide.

What is the relationship between renal function and visit-to-visit blood pressure variability in primary care? Retrospective cohort study from routinely collected healthcare data.

OBJECTIVE: To determine the relationship between renal function and visit-to-visit blood pressure (BP) variability in a cohort of primary care patients. DESIGN: Retrospective cohort study from routinely collected healthcare data. SETTING: Primary care in Nijmegen, the Netherlands, from 2007 to 2012. PARTICIPANTS: 19 175 patients who had a measure of renal function, and 7 separate visits with BP readings in the primary care record. OUTCOME MEASURES: Visit-to-visit variability in systolic BP, calculated from the first 7 office measurements, including SD, successive variation, absolute real variation and metrics of variability shown to be independent of mean. Multiple linear regression was used to analyse the influence of estimated glomerular filtration rate (eGFR) on BP variability measures with adjustment for age, sex, diabetes, mean BP, proteinuria, cardiovascular disease, time interval between measures and antihypertensive use. RESULTS: In the patient cohort, 57% were women, mean (SD) age was 65.5 (12.3) years, mean (SD) eGFR was 75.6 (18.0) mL/min/1.73m(2) and SD systolic BP 148.3 (21.4) mm Hg. All BP variability measures were negatively correlated with eGFR and positively correlated with age. However, multiple linear regressions demonstrated consistent, small magnitude negative relationships between eGFR and all measures of BP variability adjusting for confounding variables. CONCLUSIONS: Worsening renal function is associated with small increases in measures of visit-to-visit BP variability after adjustment for confounding factors. This is seen across the spectrum of renal function in the population, and provides a mechanism whereby chronic kidney disease may raise the risk of cardiovascular events.

Study Heterogeneity and Estimation of Prevalence of Primary Aldosteronism: A Systematic Review and Meta-Regression Analysis.

CONTEXT: For health care planning and allocation of resources, realistic estimation of the prevalence of primary aldosteronism is necessary. Reported prevalences of primary aldosteronism are highly variable, possibly due to study heterogeneity. OBJECTIVE: Our objective was to identify and explain heterogeneity in studies that aimed to establish the prevalence of primary aldosteronism in hypertensive patients. DATA SOURCES: PubMed, EMBASE, Web of Science, Cochrane Library, and reference lists from January 1, 1990, to January 31, 2015, were used as data sources. STUDY SELECTION: Description of an adult hypertensive patient population with confirmed diagnosis of primary aldosteronism was included in this study. DATA EXTRACTION: Dual extraction and quality assessment were the forms of data extraction. DATA SYNTHESIS: Thirty-nine studies provided data on 42 510 patients (nine studies, 5896 patients from primary care). Prevalence estimates varied from 3.2% to 12.7% in primary care and from 1% to 29.8% in referral centers. Heterogeneity was too high to establish point estimates (I(2) = 57.6% in primary care; 97.1% in referral centers). Meta-regression analysis showed higher prevalences in studies 1) published after 2000, 2) from Australia, 3) aimed at assessing prevalence of secondary hypertension, 4) that were retrospective, 5) that selected consecutive patients, and 6) not using a screening test. All studies had minor or major flaws. CONCLUSIONS: This study demonstrates that it is pointless to claim low or high prevalence of primary aldosteronism based on published reports. Because of the significant impact of a diagnosis of primary aldosteronism on health care resources and the necessary facilities, our findings urge for a prevalence study whose design takes into account the factors identified in the meta-regression analysis.

Thirty-minute compared to standardised office blood pressure measurement in general practice.

BACKGROUND: Although blood pressure measurement is one of the most frequently performed measurements in clinical practice, there are concerns about its reliability. Serial, automated oscillometric blood pressure measurement has the potential to reduce measurement bias and white-coat effect'. AIM: To study agreement of 30-minute office blood pressure measurement (OBPM) with standardised OBPM, and to compare repeatability. DESIGN AND SETTING: Method comparison study in two general practices in The Netherlands. METHOD: Thirty-minute and standardised OBPM was carried out with the same, validated device in 83 adult patients, and the procedure was repeated after 2 weeks. During 30-minute OBPM, blood pressure was measured automatically every 3 minutes, with the patient in a sitting position, alone in a quiet room. Agreement between 30-minute and standardised OBPM was assessed by Bland-Altman analysis. Repeatability of the blood pressure measurement methods after 2 weeks was expressed as the mean difference in combination with the standard deviation of difference (SDD). RESULTS: Mean 30-minute OBPM readings were 7.6/2.5 mmHg (95% confidence interval [CI] = 6.1 to 9.1/1.5 to 3.4 mmHg) lower than standardised OBPM readings. The mean difference and SDD between repeated 30-minute OBPMs (mean difference = 3/1 mmHg, 95% CI = 1 to 5/0 to 2 mmHg; SDD 9.5/5.3 mmHg) were lower than those of standardised OBPMs (mean difference = 6/2 mmHg, 95% CI = 4 to 8/1 to 4 mmHg; SDD 10.9/6.3 mmHg). CONCLUSION: Thirty-minute OBPM resulted in lower readings than standardised OBPM and had a better repeatability. These results suggest that 30-minute OBPM better reflects the patient's true blood pressure than standardised OBPM does.

A novel approach to office blood pressure measurement: 30-minute office blood pressure vs daytime ambulatory blood pressure.

PURPOSE: Current office blood pressure measurement (OBPM) is often not executed according to guidelines and cannot prevent the white-coat effect. Serial, automated, oscillometric OBPM has the potential to overcome both these problems. We therefore developed a 30-minute OBPM method that we compared with daytime ambulatory blood pressure. METHODS: Patients referred to a primary care diagnostic center for 24-hour ambulatory blood pressure monitoring (ABPM) had their blood pressure measured using the same validated ABPM device for both ABPM and 30-minute OBPMs. During 30-minute OBPM, blood pressure was measured automatically every 5 minutes with the patient sitting alone in a quiet room. The mean 30-minute OBPM (based on t = 5 to t = 30 minutes) was compared with mean daytime ABPM using paired t tests and the approach described by Bland and Altman on method comparison. RESULTS: We analyzed data from 84 patients (mean age 57 years; 61% female). Systolic and diastolic blood pressures differed from 0 to 2 mm Hg (95% confidence interval, -2 to 2 mm Hg and from 0 to 3 mm Hg) between mean 30-minute OBPM and daytime ABPM, respectively. The limits of agreement were between -19 and 19 mm Hg for systolic and -10 and 13 mm Hg for diastolic blood pressures. Both 30-minute OBPM and daytime ABPM classified normotension, white-coat hypertension, masked hypertension, and sustained hypertension equally. CONCLUSIONS: The 30-minute OBPM appears to agree well with daytime ABPM and has the potential to detect white-coat and masked hypertension. This finding makes 30-minute OBPM a promising new method to determine blood pressure during diagnosis and follow-up of patients with elevated blood pressures.

The influence of guideline revisions on the process and outcome of hypertension management in general practice: a descriptive study.

BACKGROUND: Blood pressure does not reach guideline targets in the majority of hypertensive patients. Longitudinal data from general practice records on trends in hypertension management and the influence of guideline changes are lacking. OBJECTIVE: To describe the longitudinal impact of guideline revisions on the process and outcome of hypertension management in a primary care based database. METHODS: We extracted data from the Nijmegen Monitoring Project (NMP), an academic practice-based research network with 50,000 patients listed. Based on the years of publication of the first Dutch guideline on hypertension (1991) and two revisions (1997 and 2003), we formed three cohorts of patients newly diagnosed with hypertension. We compared data such as patient characteristics, 2-year blood pressure course, type of first-choice antihypertensive drugs, and number of medications after 2 years of treatment. RESULTS: Both the mean age at time of diagnosis of hypertension and pulse pressure rose between cohorts. In agreement with revisions in the guidelines, the use of diuretics as first-choice drugs increased significantly from the first to the last cohort. The percentage of patients with three or more antihypertensive drugs remained equal. The relative 2-year systolic blood pressure decline did not differ with clinical relevance between the cohorts. CONCLUSION: Our study has demonstrated that general practitioners achieve substantial and prolonged blood pressure reduction. However, guideline revisions do not seem to influence the amount of reduction, despite clear formulation of stricter treatment goals. In addition to qualitative research to identify the causes of this phenomenon, research to evaluate the effect of expert support systems on risk awareness and risk gain by additional treatment is necessary.

Non-cardiovascular co-morbidity in elderly patients with heart failure outnumbers cardiovascular co-morbidity.

BACKGROUND: Patients with heart failure often suffer from multiple co-morbid conditions. However, until now only cardiovascular co-morbidity has been well described. AIMS: To understand heart failure in the context of multi-morbidity, by describing the age and sex specific patterns of non-cardiovascular co-morbidity in elderly patients with heart failure in general practice. METHODS: All patients aged 65 years and over, diagnosed with heart failure in four practices of the Nijmegen Academic Practice-based Research Network (NPBRN) between January 1999 and December 2003 were selected, and the prevalence of 27 cardio- and non-cardiovascular co-morbidities determined. RESULTS: Of the 269 patients identified (mean age 79 years; 57% women), 80.2% had four or more co-morbidities. With increasing age, a significant increase in the prevalence of non-cardiovascular conditions like visual and hearing impairments, osteoarthritis, dementia and urine incontinence; and a decrease in cardiovascular conditions like myocardial infarction and in women, hypertension, was observed. In patients aged 85 years and over, non-cardiovascular disorders predominated over cardiovascular disorders. CONCLUSIONS: In elderly patients with heart failure, the prevalence of non-cardiovascular co-morbidity is very high and exceeds the prevalence of cardiovascular conditions. Diseases such as dementia and osteoarthritis must be taken into account in the management of elderly patients with heart failure.