Showing papers by "Roland E. Schmieder published in 2015"

Effect of finerenone on albuminuria in patients with diabetic nephropathy : a randomized clinical trial

Abstract: Importance Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events. Objective To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug. Interventions Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days. Main Outcomes and Measures The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate. Results The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m 2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P P Conclusions and Relevance Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications. Trial Registration clinicaltrials.gov Identifier:NCT1874431

First Report of the Global SYMPLICITY Registry on the Effect of Renal Artery Denervation in Patients With Uncontrolled Hypertension

Abstract: This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, ≥160 mm Hg; 24-hour systolic pressure, ≥135 mm Hg; and ≥3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5±24.0 mm Hg for all patients and 179.3±16.5 mm Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5±17.0 and 159.0±15.6 mm Hg. At 6 months, the changes in office and 24-hour systolic BPs were −11.6±25.3 and −6.6±18.0 mm Hg for all patients ( P P 70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT01534299

Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design.

Abstract: Approximately 8–18% of all patients with high blood pressure (BP) are apparently resistant to drug treatment.1,2 In this situation, new strategies to help reduce BP are urgently needed but the complex pathophysiology of resistant hypertension makes this search difficult. Not surprisingly in this context, the latest non-drug treatment which triggered controversy is catheter-based renal denervation (RDN).3,4 The method uses radiofrequency energy, or alternatively ultrasound or chemical denervation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.5,6 Various experimental models of hypertension strongly support this concept7,8 and available evidence also suggests that sympathetic nervous system activation contributes to the development and progression of hypertension and subsequently to target organ damage.7–11 Historical observations have shown that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.12,13 However, the clinical evidence in support of RDN as an effective interventional technique in patients with resistant hypertension is conflicting. A number of observational studies and three randomized, controlled trials (Symplicity HTN-2, Prague-15, and DENERHTN) support both safety and efficacy of this new therapy14–22 but some smaller studies and the large, single-blind, randomized, sham-controlled symplicity HTN-3 trial failed to show superiority of RDN when compared with medical therapy alone.23–25 Whatever the shortcomings of individual trials may be, the possibility remains that the observed BP responses were due to placebo response, the Hawthorne effect, regression to the mean, unknown co-interventions or other bias.26 The design, conduct, and interpretation …

Reduced Effect of Percutaneous Renal Denervation on Blood Pressure in Patients With Isolated Systolic Hypertension

Abstract: Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, ≥140/<90 mm Hg) is unknown. This study investigated the effects of renal denervation in 126 patients divided into 63 patients with ISH and 63 patients with combined hypertension (CH, ≥140/≥90 mm Hg) defined as baseline office systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 antihypertensive agents. Renal denervation significantly reduced office SBP and diastolic blood pressure (DBP) at 3, 6, and 12 months by 17/18/17 and 5/4/4 mm Hg in ISH and by 28/27/30 and 13/16/18 mm Hg in CH, respectively. The reduction in SBP and DBP in ISH was lower compared with patients with CH at all observed time points (P<0.05 for SBP/DBP intergroup comparison). The nonresponder rate (change in office SBP <10 mm Hg) after 6 months was 37% in ISH and 21% in CH (P<0.001). Mean 24-hour ambulatory SBP and DBP after 3, 6, and 12 months were significantly reduced by 10/13/15 and 6/6/9 mm Hg in CH, respectively. In patients with ISH the reduction in systolic ambulatory blood pressure was 4/8/7 mm Hg (P=0.032/P<0.001/P=0.009) and 3/4/2 mm Hg (P=0.08/P<0.001/P=0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH.

Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.

Abstract: Objectives Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatment-resistant hypertension. Methods We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) ≥ 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement ≥ 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at http://www.clinicaltrials.gov (ID: NCT01442883). Results Mean baseline BP was 156 ± 12/82 ± 13 mmHg, despite treatment with 6.2 ± 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 ± 20 (P Conclusions Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function.

Systolic Blood Pressure Variation and Mean Heart Rate Is Associated With Cognitive Dysfunction in Patients With High Cardiovascular Risk

Abstract: — Elevated systolic blood pressure (SBP) correlates to cognitive decline and incident dementia. The effects of heart rate (HR), visit to visit HR variation, and visit to visit SBP variation are less well established. Patients without preexisting cognitive dysfunction (N=24 593) were evaluated according to mean SBP, SBP visit to visit variation (coefficient of variation [standard deviation/mean×100%], CV), mean HR, and visit to visit HR variation (HR-CV) in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. Cognitive function was assessed with mini mental state examination. Cognitive dysfunction (fall in mini mental state examination ≤24 points), important cognitive decline (drop of ≥5 points), and cognitive deterioration (drop of >1 point per year or decline to 24 points) were assessed. SBP and HR were measured over 10.7±2.2 (mean±SD) visits. Mean SBP, mean HR, and SBP-CV were associated with cognitive decline, dysfunction, and deterioration (all P P =0.0030) and mean HR ( P =0.0008) remained predictors for cognitive dysfunction (odds ratios [95% confidence intervals], 1.32 [1.10–1.58] for 5th versus 1st quintile of SBP-CV and 1.40 [1.18–1.66] for 5th versus 1st quintile of mean HR). Similar effects were observed for cognitive decline and deterioration. SBP-CV and mean HR showed additive effects. In conclusion, SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00153101.

New developments in the pathogenesis of obesity-induced hypertension.

Abstract: Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of α-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity.

Cost of poor adherence to anti-hypertensive therapy in five European countries

Abstract: The financial burden for EU health systems associated with cardiovascular disease (CV) has been estimated to be nearly €110 billion in 2006, corresponding to 10 % of total healthcare expenditure across EU or a mean €223 annual cost per capita. The main purpose of this study is to estimate the costs related to hypertension and the economic impact of increasing adherence to anti-hypertensive therapy in five European countries (Italy, Germany, France, Spain and England). A probabilistic prevalence-based decision tree model was developed to estimate the direct costs of CV related to hypertension (CV defined as: stroke, heart attack, heart failure) in five European countries. Our model considered adherence to hypertension treatment as a main driver of blood pressure (BP) control (BP < 140/90 mmHg). Relative risk of CV, based on controlled or uncontrolled BP group, was estimated from the Framingham Heart Study and national review data. Prevalence and cost data were estimated from national literature reviews. A national payer (NP) perspective for 10 years was considered. Probabilistic sensitivity analysis was performed in order to evaluate uncertainty around the results (given as 95 % confidence intervals). The model estimated a total of 8.6 million (1.4 in Italy, 3.3 in Germany, 1.2 in Spain, 1.8 in France and 0.9 in England) CV events related to hypertension over the 10-year time horizon. Increasing the adherence rate to anti-hypertensive therapy to 70 % (baseline value is different for each country) would lead to 82,235 fewer CV events (24,058 in Italy, 7,870 in Germany, 18,870 in Spain, 24,855 in France and 6,553 in England). From the NP perspective, the direct cost associated with hypertension was estimated to be €51.3 billion (8.1 in Italy, 17.1 in Germany, 12.2 in Spain, 8.8 in France and 5.0 in England). Increasing adherence to anti-hypertensive therapy to 70 % would save a total of €332 million (CI 95 %: €319–346 million) from the NPs perspective. This study is the first attempt to estimate the economic impact of non-adherence amongst patients with diagnosed hypertension in Europe, using data from five European countries (Italy, France, Germany, Spain and England).

Central pulse pressure predicts BP reduction after renal denervation in patients with treatment-resistant hypertension.

Abstract: AIMS Enhanced vascular ageing is associated with elevated central pulse pressure (cPP), an independent predictor of cardiovascular (CV) events. Although antihypertensive treatment strategies are effective, high residual CV risk remains indicative of advanced and largely irreversible vascular damage. Renal denervation (RDN) has been shown to reduce blood pressure (BP) to various extents in patients with treatment-resistant hypertension (TRH). We hypothesised that cPP predicts BP reduction after RDN. METHODS AND RESULTS Sixty-three patients with true TRH underwent catheter-based RDN using the Symplicity Flex™ catheter and were followed for six months. At baseline, cPP was assessed by pulse wave analysis (SphygmoCor™). Patients were stratified according to their median cPP (55 mmHg), and called "low cPP" (below the median) or "high cPP" (above the median). Office BP reduction six months after RDN was greater (-22±19/-13±11 vs. -12±20/-5±13 mmHg, p=0.038/0.014) and 24-hr ambulatory blood pressure (ABP) reduction tended to be greater (-11±13/-8±10 vs. -3±18/-4±10 mmHg, p=0.070/0.112) in patients with low cPP compared to those with high cPP. Only cPP (β=0.687, p=0.001) and baseline systolic BP (β=-0.564, p<0.001) were independent determinants of office systolic BP reduction after RDN. CONCLUSIONS Our data suggest that cPP, indicative of the degree of large arterial stiffening, may be helpful to identify responders to RDN.

Resting heart rate is associated with renal disease outcomes in patients with vascular disease: results of the ONTARGET and TRANSCEND studies

Abstract: Background Resting heart rate (RHR) is associated with cardiovascular disease outcomes in high-risk patients. It is not known whether RHR is predictive of renal outcomes such as albuminuria, end-stage renal disease (ESRD) or doubling of creatinine. We evaluated whether RHR could predict renal endpoints in patients at a high risk of cardiovascular disease. We also tested the effects of RHR at different levels of systolic blood pressure (SBP). Methods We analysed data from 28 757 patients in the ONTARGET and TRANSCEND trials. RHR and SBP were available for a mean of 4.9 ± 0.4 visits (range 3–5) within the first 2 years of the studies. Albuminuria was determined at baseline, at 2 years and at study end. Results Mean RHR was predictive of incident micro-albuminuria [hazard ratio (HR) for RHR ≥80 vs. <60 beats min−1 1.49, 95% confidence interval (CI) 1.29–1.71, P < 0.0001], incident macro-albuminuria (HR 1.84, 95% CI 1.39–2.42, P < 0.0001), doubling of creatinine (HR 1.47, 95% CI 1.00–2.17, P = 0.050) and ESRD (HR 1.78, 95% CI 1.00–3.16, P = 0.050), and the combined renal end-point (HR 1.51, 95% CI 1.32–1.74, P < 0.0001). Associations were robust at SBPs from <120 to ≥150 mmHg, with the lowest risk at a SBP of 130–140 mmHg. Conclusion Resting heart rate is a potent predictor of these renal outcomes, as well as their combination, in patients with cardiovascular disease. RHR at all SBP levels should be considered as a possible renal disease risk predictor and should be investigated as a treatment target with RHR-reducing agents.

Effects of renal sympathetic denervation on urinary sodium excretion in patients with resistant hypertension

Abstract: Sympathetic overactivity increases sodium retention and contributes to the pathophysiology of hypertension. Renal sympathetic denervation lowers blood pressure and reduces sympathetic activity in certain patients with resistant hypertension. This study aimed to assess the effect of renal denervation on urinary sodium excretion. 24-h urinary sodium excretion was estimated at baseline and after 6 months using the Kawasaki formula in 137 patients with resistant hypertension undergoing renal denervation. Sodium excretion was adjusted for cystatin C GFR and fractional sodium excretion was assessed. Mean office systolic blood pressure at baseline was 171 ± 2 mmHg despite an intake of 5.2 ± 0.1 antihypertensive drugs. Six months after renal denervation, systolic and diastolic BP decreased by 18 ± 2 mmHg (p < 0.0001) and 10 ± 1 mmHg (p < 0.001). 90 patients (65.7 %) had SBP reductions ≥10 mmHg (responders). After 6 months, 24-h UNa increased by 13 % compared to baseline (236 ± 9 vs. 268 ± 9 mmol/day, p < 0.003). This increase was most pronounced in patients with less response in BP. These findings were paralleled by a significant increase in fractional sodium excretion (1.19 ± 0.11 vs. 1.64 ± 0.14 %, p < 0.0001) and were observed independently of the intake of antihypertensive drugs affecting sodium balance, such as mineralocorticoid receptor antagonists or diuretics. RDN lowered BP and increased estimated UNa and fractional sodium excretion in patients with resistant hypertension independently of renal function and antihypertensive therapy.

Wilder's principle: pre-treatment value determines post-treatment response

Abstract: Over more than half a century numerous studies have documented that pre-treatment blood pressure (BP) is a determinant of the anti-hypertensive response.1–9 This has been shown for systolic and diastolic BP, acute and long-term response, monotherapy and combination therapy, and for office BP as well as for 24 h ambulatory BP. The first observation along that line was perhaps made by Freis et al . who, in 1958, in a very careful in-patient study reported a decrease in BP with chlorothiazide in every single hypertensive patient whereas in 15 normotensive subjects followed under exactly similar dietary and hospital control conditions, no reduction in BP occurred.10 This phenomenon that the pre-treatment level determines to a large extent the change per se , that is, the principle of initial value (German: Ausgangswertgesetz) was first described by Josef Wilder in 1931 who proposed that the ‘direction of response of body function to any agent depends to a large degree on the initial valuable of that function’.11,12 In 1976, Dixon and Johnson put forward the hypothesis that ‘the magnitude of the fall in blood-pressure in response to an antihypertensive drug depends on the level of the pretreatment pressure, and there is a direct relationship between the two in that the higher the pretreatment pressure the greater the fall in pressure in response to treatment’.13 Subsequent testing of this hypothesis in 42 published small studies in a total of 971 patients with 23 anti-hypertensive drug regimens revealed that in clinical practice ‘most of the regimens failed to show ideal behavior’ but that the ‘hypothesis …

Renal impairment and worsening of renal function in acute heart failure: can new therapies help? The potential role of serelaxin.

Abstract: Renal dysfunction is a frequent finding in patients with acute heart failure (AHF) and an important prognostic factor for adverse outcomes. Worsening of renal function occurs in 30–50 % of patients hospitalised for AHF, and is associated with increased mortality, prolonged hospital stay and increased risk of readmission. Likely mechanisms involved in the decrease in renal function include impaired haemodynamics and activation of neurohormonal factors, such as the renin–angiotensin–aldosterone system, the sympathetic nervous system and the arginine–vasopressin system. Additionally, many drugs currently used to treat AHF have a detrimental effect on renal function. Therefore, pharmacotherapy for AHF should carefully take into account any potential complications related to renal function. Serelaxin, currently in clinical development for the treatment of AHF is a recombinant form of human relaxin-2, identical in structure to the naturally occurring human relaxin-2 peptide hormone that mediates cardiac and renal adaptations during pregnancy. Data from both pre-clinical and clinical studies indicate a potentially beneficial effect of serelaxin on kidney function. In this review, we discuss the mechanisms and impact of impairment of renal function in AHF, and the potential benefits of new therapies, such as serelaxin, in this context.

Low resting heart rates are associated with new‐onset atrial fibrillation in patients with vascular disease: results of the ONTARGET/TRANSCEND studies

Abstract: Background Elevated systolic blood pressure (SBP) and high resting heart rate (HR) are associated with cardiovascular end-points. Although the association between atrial fibrillation (AF) and SBP is well established, the relation between AF and HR remains unclear. Methods In patients from the ONTARGET and TRANSCEND studies with high cardiovascular disease risk (n = 27 064), new-onset AF was evaluated in relation to mean SBP, visit-to-visit variation in SBP (SBP-CV; i.e. SD/mean × 100%), mean HR and visit-to-visit variation in HR (HR-CV). Results Low mean HR (P < 0.0001) and high SBP (P = 0.0021) were associated with incident AF. High SBP-CV (P = 0.031) and HR-CV (P < 0.0001) were also associated with incident AF. After adjustment for confounders, SBP and SBP-CV were no longer significantly associated with AF. The detrimental effect of low HR was particularly evident in subjects who were not receiving treatment with beta-blockers (P = 0.014 for interaction between beta-blocker use and mean HR). In addition to low HR, high HR-CV and high SBP had additive effects on incident AF. Conclusions Low mean HR (<60 beats min−1) is independently associated with incident AF, and low HR-CV and high SBP further increase the incidence of new-onset AF in patients at high risk of cardiovascular disease.

Effect of aliskiren on vascular remodelling in small retinal circulation.

Abstract: Background:In hypertension, changes in small arterial structure are characterized by an increased wall-to-lumen ratio (WLR). These adaptive processes are modulated by the rennin–angiotensin system. It is unclear whether direct renin inhibitors exert protective effects on small arteries in hypertensi

Cost of poor adherence to anti-hypertensive therapy in five European countries

Abstract: The financial burden for EU health systems associated with cardiovascular disease (CV) has been estimated to be nearly €110 billion in 2006, corresponding to 10 % of total healthcare expenditure across EU or a mean €223 annual cost per capita. The main purpose of this study is to estimate the costs related to hypertension and the economic impact of increasing adherence to anti-hypertensive therapy in five European countries (Italy, Germany, France, Spain and England). A probabilistic prevalence-based decision tree model was developed to estimate the direct costs of CV related to hypertension (CV defined as: stroke, heart attack, heart failure) in five European countries. Our model considered adherence to hypertension treatment as a main driver of blood pressure (BP) control (BP

Achievement of individualized treatment targets in patients with comorbid type-2 diabetes and hypertension: 6 months results of the DIALOGUE registry.

Abstract: Background Patients with type-2 diabetes mellitus (T2DM) and hypertension have increased risk of cardiovascular disease (CVD). We studied individualized treatment targets and their achievement in clinical practice.

Circadian rhythm and day to day variability of serum potassium concentration: a pilot study.

Abstract: Hyperkalemia is a common and life-threatening complication frequently seen in patients with acute kidney injury, end-stage renal disease and chronic heart failure. Cardiac arrest and ventricular fibrillation are possible consequences. Biosensors are currently being developed to measure serum potassium under ambulatory conditions and trigger an alarm if the potassium concentration exceeds normal limits. Only few studies exist on the circadian rhythm of potassium; and its dependence on age and kidney function is less clear. Our observational monocentric exploratory study included 30 subjects of which 15 had impaired renal function (RF) (GFR <60 ml/min/1.73 m2). Subjects were further categorized into three age groups: 18–39 years (N normal RF = 5, N impaired RF = 4), 40–59 years (N normal RF = 5, N impaired RF = 6), 60–80 years (N normal RF = 5, N impaired RF = 5). Serum potassium levels were measured every 2 h during a 24 h period and repeated once after 2, 4, or 6 days. In the 15 subjects with normal RF, the lowest mean potassium level (3.96 ± 0.14 mmol/l) was observed at 9 p.m. and the greatest (4.23 ± 0.23 mmol/l) at 1 p.m. In patients with impaired RF the lowest mean potassium level (4.20 ± 0.32 mmol/l) was observed at 9 p.m. and the highest (4.57 ± 0.46 mmol/l) at 3 p.m. The range between the mean of minimum and maximum was greater in patients with impaired RF (0.71 ± 0.45 mmol/l) than in subjects with normal RF (0.53 ± 0.14 mmol/l) [p < 0.001]. No difference in the circadian rhythm was found between the first and second examination. Our results indicate that patients with normal and impaired RF have comparable circadian patterns of serum potassium concentrations, but higher fluctuations in patients with impaired RF. These results have clinical relevance for developing an automatic biosensor to measure the potassium concentration in blood under ambulatory conditions in patients at high risk for potassium fluctuations.

Renal Denervation for Resistant Hypertension: Past, Present, and Future

Abstract: Renal denervation (RDN) for treatment of resistant hypertension was introduced only 5 years ago. A clear pathophysiological role of renal sympathetic activity for the initiation and maintenance of hypertension and promising data showing a substantial and sustained blood pressure (BP) reduction after RDN has promoted the widespread use of the method at least in Europe. However, in a pivotal trial that included a sham-control group, no significant BP lowering effects was observed. Afterwards, it became clear that methodological issues and poor performance and execution of the intervention have hampered the results of Symplicity HTN-3 study, thereby limiting its validity profoundly. Now, in 2015, the renaissance of RDN has begun and new randomized prospective clinical trials have or will be started soon. In the meantime, it may be wise not to ignore all previous findings, as a rescue therapy for treatment resistant hypertension. A new science era emerged, with changes of the interventional approach and selection of patients potentially profiting most from RDN.

Olmesartan improves pulse wave velocity and lowers central systolic blood pressure and ambulatory blood pressure in patients with metabolic syndrome.

Abstract: Ambulatory blood pressure (BP) and central systolic BP (cSBP) are superior to brachial office BP measurements in predicting cardiovascular end organ damage. The authors aimed to analyze the effect of olmesartan 80 mg (OLM 80) vs 20 mg (OLM 20) vs amlodipine 5 mg (AML 5) on central hemodymamics and ambulatory BP in patients with metabolic syndrome (MetS).In a double-blind, three-phase crossover study comprising 69 untreated patients with MetS defined by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults guidelines, the effects of OLM 80 on central hemodynamics (cSBP), central pulse pressure), pulse wave velocity (PWV), and 24-hour ambulatory BP were compared with OLM 20 and AML 5, given for 6 weeks each. In 69 patients (47 men, 22 women) (51.5±9.75 years), reduction in cSBP was the highest with OLM 80 and significantly greater than the reduction with AML 5 (-14.1 mm Hg vs -9.7 mm Hg, P=.0117). All three substances significantly reduced 24-hour ambulatory systolic (OLM 80 and OLM 20 P<.0001; AML 5 P=.0105). BP and 24-hour diastolic BP (OLM 80 and OLM 20 P<.0001; AML 5 P=.0126). PWV was significantly reduced by OLM 80 (-0.58 m/s, P=.0088) and by OLM 20 (-0.48 m/s, P=.0362) but not by AML 5 (-0.28 m/s, P=.2065). For PWV, no significant differences were detected between the three groups. OLM significantly improves arterial stiffness as demonstrated by the reduction in PWV and in cSBP. In addition, 24-hour ambulatory BP was reduced to a greater extent with OLM 80 than with AML 5.

Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry.

Abstract: For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors.

Aldosterone Antagonists and Renal Denervation: Friends or Foes?

Abstract: See related article, pp 407–413 Activation of the sympathetic nervous system plays an important role in the development and disease progression of hypertension and its comorbidities.1 Antihypertensive treatment approaches have focused on abrogation of activated neurohormonal systems associated with these conditions, including the renin–angiotensin–aldosterone system and the sympathetic nervous system. Despite the availability of effective antihypertensive drugs, certain patients remain uncontrolled to target blood pressure (BP) values.2 For these patients with uncontrolled hypertension, new device-based treatments have been developed, such as surgically implanted baroreceptor stimulators and catheter-based renal denervation.3 The available evidence suggests that renal denervation reduces renal sympathetic activity and office BP, as well as ambulatory BP in open-label registries and randomized, controlled trials in certain patients, but not in all patients.4 The BP-lowering effect of intensified drug treatment, with special focus on aldosterone antagonist treatment, compared with catheter-based renal denervation has not been investigated in detail. In this issue, the prospective, randomized, open-label multicenter PRAGUE-15 trial by Rosa et al5 investigated the efficacy and safety of catheter-based renal denervation (using Medtronic’s Symplicity device) versus intensified pharmacological treatment, including spironolactone in patients with mild to moderate resistant hypertension (office systolic BP [SBP] at the baseline, >140 mm Hg; 24-hour BP at the baseline, >130 mm Hg). The adherence of patients was confirmed by plasma toxicological analyses at the beginning (but unfortunately not after 6 months), and secondary causes of hypertension were excluded systematically. The study provides interesting insights about the efficacy and safety of intensified drug treatment and catheter-based renal denervation in patients with resistant hypertension. The significant BP change (24-hour SBP, −8.1 mm Hg; P =0.001 and office SBP, −14.3 mm Hg; P <0.001) in the intensified drug treatment group of PRAGUE-15 was mostly driven by patients in whom spironolactone was added and …

Effect of Telmisartan on Renal Outcomes

Abstract: Results: No important difference was found in the composite renal outcome with telmisartan (58 patients [1.96%]) versus placebo (46 patients [1.55%]) (hazard ratio, 1.29 [95% CI, 0.87 to 1.89]; P 0.20). Among the telmisartan and placebo groups, 7 and 10 patients had dialysis and 56 and 36 patients had doubling of serum creatinine, respectively (hazard ratio, 1.59 [CI, 1.04 to 2.41]; P 0.031). Albuminuria increased less with telmisartan than with placebo (32% [CI, 23% to 41%] vs. 63% [CI, 52% to 76%]; P 0.001). Decreases in estimated GFR were greater with telmisartan than with placebo (mean change in estimated GFR, 3.2 mL/min per 1.73 m 2 [SD, 18.3] vs. 0.26 mL/min per 1.73 m 2 [SD, 18.0];

Retinal microperfusion after renal denervation in treatment-resistant hypertensive patients

Abstract: High pulsatile pressure and flow in the arteries causes microvascular damage, and hence increased cardio-, and cerebrovascular complications. With advanced stages of hypertensive disease, an exaggerated pulsatile retinal capillary flow (RCF) has been shown, but data about interventional effect are missing. Fifty-one patients with true treatment-resistant hypertension (TRH) underwent renal denervation (RDN) using the Symplicity Flex™ catheter and were followed for 12 months. RCF was assessed non-invasively using Scanning laser Doppler flowmetry (SLDF) before, 6 (6 M), and 12 (12 M) months after RDN. RCF was measured in systole and diastole and pulsed RCF (difference of RCF in systole minus diastole) was calculated. In addition, flicker light-induced vasodilation (representing vasodilatory capacity) was assessed. Systolic and diastolic office blood pressure (BP) as well as 24-h ABPM decreased significantly 6 M and 12 M after RDN, compared to baseline values (all p < 0.001). There was a significant reduction of pulsed RCF 6 M (231 ± 81 versus 208 ± 68 AU, p = 0.046) and 12 M (194 ± 72 AU, p = 0.001) after RDN, whereas the mean RCF was unchanged. Moreover, there was a significant increase of flicker light-induced vasodilation after RDN (p = 0.043). In hypertensive patients with TRH, we observed a decrease of pulsed RCF 6 M and 12 M after RDN and an increase of vasodilatory capacity, in parallel to decreases in BP and heart rate. The reduction of pulsed RCF after RDN implies a decrease of shear stress on the vascular wall by the pulsed blood flow. This and the increment of vasodilatory capacity suggest an improvement of retinal (and potentially cerebral) microcirculation.

The renin-angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril in clinical trials versus routine practice: insights from the prospective EARLY registry.

Abstract: Patient characteristics and blood pressure-related outcomes in randomized clinical trials (RCTs) differ from clinical practice because of stringent selection criteria. The present study aimed to explore the relationship between clinical trials and clinical practice. We analyzed data from patients enrolled in the “Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry comparing blood pressure (BP) effects of the angiotensin receptor blocker (ARB) azilsartan medoxomil (AZL-M) with the angiotensin-converting enzyme (ACE) inhibitor ramipril between patients who met the eligibility criteria of a previous RCT and those who did not. Patients with primary arterial hypertension were consecutively enrolled from primary care offices in Germany into the EARLY registry in a 7:3 ratio for treatment with AZL-M or an ACE inhibitor, provided that they met the following criteria at baseline: 1) no antihypertensive treatment prior to inclusion or a non-renin-angiotensin system (RAS) based monotherapy; 2) initiation of treatment with either AZL-M or an ACE inhibitor alone. Analyses were performed to evaluate BP effects for patients in the EARLY registry who met the selection criteria of a prior RCT (RCT+) versus those who did not (RCT-). Out of 3,698 patients considered, 1,644 complied with the RCT criteria (RCT+) while 2,054 did not (RCT-). RCT- patients (55.5 %) displayed a higher risk profile in terms of age and comorbidities, and a wider spectrum of BP values at baseline, as highlighted by the grades of hypertension and mean BP values. The proportion of patients who achieved target blood pressure control in the RCT+ group was significantly higher for AZL-M versus ramipril (64.1 versus 56.1 %; P < 0.01), in accordance with the result of the clinical trial. In the RCT- AZL-M group, the proportion of patients who met BP targets was lower (58.1 %) than in the RCT+ AZL-M group (64.1 %), whereas the proportion of patients with target BP values in the RCT- ramipril and the RCT+ ramipril groups was similar (57.7 versus 56.1 %). Thus, in contrast to results for the RCT+ group, in the RCT- group, the target BP attainment rate for AZL-M was not significantly superior to that for ramipril. However, the tolerability profile of AZL-M and ramipril was comparable in both populations. At the 12-month follow-up, death and stroke rates were low (≤0.5 %) and adverse events did not differ between the AZL-M and ramipril groups, irrespective of RCT eligibility. These data confirm that the EARLY population comprised a broader spectrum of hypertensive patients than RCTs, and the differences in patient characteristics were accompanied by disparate rates of blood pressure goal attainment. Overall, the validity of the RCT was demonstrated and confirmed in clinical practice with a broader range of patients with various comorbidities.

Retinal Circulation in Arterial Disease

Abstract: Hypertension provokes structural and functional alterations of the retinal vasculature. The analysis of retinal vasculature provides the unique opportunity to examine microvascular changes noninvasively in humans. Large epidemiological studies using retinal photographs have assessed the association between vascular alterations of the retinal circulation and blood pressure, target organ damage, and cardiovascular events. Nowadays, innovative methods (e.g., scanning laser Doppler flowmetry) enable the assessment of the arteriolar wall directly (i.e., vascular remodeling) as well as changes of vascular tone (i.e., endothelial function). Based on such an assessment of early vascular remodeling processes, it may be possible in future to individualize antihypertensive therapy of patients. Since the retinal circulation is thought to mirror the cerebral circulation, these innovative approaches to measure vascular changes in hypertension early and individually may lead to more effective strategies to prevent cerebrovascular events.

Reply to comment on Cost of poor adherence to anti-hypertensive therapy in five European country.

Abstract: We wish to thank the Editor for giving us the opportunity to respond to the points raised by Prof. Afschin Gandjour, who has questioned the repeatability of the results based on the input data listed in the publication. Prof. Gandjour illustrates his point of view suggesting two steps to estimate the net cost of making one additional patient adherent to blood pressure (BP) treatment. Our model is based on the decision tree described in Fig. 1 of the article [1], which we used alongside the data reported in Tables 1 and 2 of the article to populate the model and simulate the results. For example, consider the case of a diagnosed female in Italy. Figure 1 summarizes the decision tree for an Italian subject who has an adherence equal to 41.5 % (red cell in the figure). Event probabilities (light green cell) were reported considering the data in Table 1 of our article [1], while probability transitions for the controlled and uncontrolled state (light blue cell) were extrapolated from Table 2 of our article [1]. Applying these parameters to the population estimated in Italy (yellow cell), we estimated the number of events for each sex and disease state (Fig. 2). Finally, subjects were multiplied by €280 and events were multiplied by €3.393 (Table 3 of the article) assuming that all patients diagnosed were treated, with the only difference being that some patients had lower adherence (\80 %) than others. Applying the same methods to consider a scenario with increasing adherence for diagnosed subjects, we estimated the costs after 10 years in case of adherence equal to 70 % (red cell in Fig. 3). Table 1 summarizes the results for male and female diagnosed subjects in Italy considering the simulation previously described. Total costs reported in Table 1 are available in Table 4 of our article [1]. Regarding the first point commented on by Prof. Gandjour, the ‘‘transparency and repeatability of the results,’’ we hope that Figs. 1, 2 and 3 clarify the method This reply refers to the article available at doi:10.1007/s10198-015-0713-x.

[Renal denervation in refractory hypertension: joint statement of the German hypertension league DHL eV and the German societies of cardiology, angiology, nephrology and radiology].

Abstract: Die arterielle Hypertonie stellt einen bedeutenden Risikofaktor fur die kardiovaskulare Sterblichkeit dar und ist trotz der Verfugbarkeit effizienter Medikamente in Deutschland unzureichend kontrolliert. Die Schein-Prozedur kontrollierte Symplicity HTN-3 Studie erreichte den Sicherheitsendpunkt, verfehlte jedoch den primaren Effektivitatsendpunkt. Die Fachgesellschaften vertreten den Standpunkt, dass die renale Denervation keine Alternative zu einer etablierten nicht medikamentosen und medikamentosen Therapie darstellt. Sie ist bei therapierefraktaren Patienten im Einzelfall als zusatzliches Verfahren zu sehen und bleibt spezialisierten Zentren vorbehalten. Die renale Denervation muss in randomisierten, kontrollierten Studien weiter kritisch evaluiert werden