Adherence to antihypertensive medication in renal denervation trials: new studies, old problems?

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Anatomische und prozedurale Determinanten einer Blutdruckreduktion nach kathetergestützter renaler Denervation bei Patienten mit therapieresistenter Hypertonie

Hintergrund: Die arterielle Hypertonie ist einer der wichtigsten kardiovaskulären Risikofaktoren und mit Morbidität und Sterblichkeit assoziiert. Kenntnisse der Nierenarterienanatomie sind für das pathophysiologische Verständnis der arteriellen Hypertonie ebenso von Bedeutung wie für die Entwicklung und Verbesserung interventioneller Therapieoptionen. Allerdings liegen weder ausreichende Daten zur Nierenarterienanatomie vor, noch ist eine standardisierte und allgemein gebräuchliche Nomenklatur der Nierenarterien vorhanden. Die kathetergestützte renale Denervation wurde entwickelt, um die sympathische Nervenaktivität hypertensiver Patienten zu reduzieren und somit eine Blutdrucksenkung zu induzieren. Die Variabilität der individuellen Blutdruckänderung nach renaler Denervation verdeutlicht die Notwendigkeit weiterführender Untersuchungen zur Identifikation von prozeduralen und anatomischen Prädiktoren eines therapeutischen Ansprechens auf den Eingriff. Methoden: Im Rahmen einer multizentrischen Studie wurde zwischen März 2009 und Juni 2013 bei 1000 hypertensiven Patienten in neun internationalen Zentren eine selektive Renovasographie durchgeführt und hierbei eine neu konzipierte Nomenklatur der Nierenarterien angewendet. Alle Angiographien wurden mittels quantitativer vaskulärer Analyse ohne Kenntnis der Patientencharakteristika ausgewertet. Darüber hinaus wurden 150 Patienten mit therapieresistenter Hypertonie am Universitätsklinikum des Saarlandes einer renalen Denervation unterzogen. Die prozeduralen Parameter wurden erfasst. Nierenarterienanatomie: Die 1000 hypertensiven Patienten hatten einen durchschnittlichen Praxisblutdruck von 168/90±26/17 mmHg. Die rechte Hauptnierenarterie war länger als die linke (41±15 vs. 35±13 mm, p<0,001), wohingegen die linke einen größeren Diameter aufwies (5,4±1,2 vs. 5,2±1,2 mm, p<0,001). Akzessorische Nierenarterien wurden bei 22% der Patienten und eine renovaskuläre Erkrankung bei 9% der Patienten dokumentiert. Patienten mit unkontrollierter Hypertonie (Praxisblutdruck ³140/90 mmHg) hatten durchschnittlich eine längere linke Hauptnierenarterie (+2,7 mm, p=0,034) als Patienten mit kontrollierter Hypertonie. Alle anderen anatomischen Parameter der Nierenarterien von Patienten mit und ohne Blutdruckkontrolle unterschieden sich nicht signifikant. Patienten mit eingeschränkter Nierenfunktion (geschätzte glomeruläre Filtrationsrate <90 ml/min) hatten im Diameter kleinere Hauptnierenarterien als Nierengesunde (links -0,5 mm, rechts -0,4 mm, jeweils p<0,001). Determinanten einer Blutdruckreduktion nach renaler Denervation: Akzessorische Nierenarterien lagen bei 37% der Patienten und eine renovaskuläre Erkrankung bei 9% der Patienten vor. Sechs Monate nach renaler Denervation wurde der 24-Stunden- Langzeitblutdruck um 11/6 mmHg (jeweils p<0,001) reduziert. Das Ausmaß der Reduktion des systolischen Blutdrucks war unabhängig vom Vorliegen akzessorischer Nierenarterien (p=0,543) oder einer renovaskulären Erkrankung (p=0,598). Patienten mit mindestens einer Hauptnierenarterie mit einem Diameter £4 mm wiesen eine deutlichere Reduktion des systolischen 24-Stunden-Langzeitblutdrucks als Patienten mit größeren Hauptnierenarterien auf (-19 versus -10 mmHg, p=0,038). Weder die Länge der Nierenarterien noch die Anzahl der Ablationspunkte beeinflusste die Blutdruckreduktion sechs Monate nach renaler Denervation. Schlussfolgerung: Die Nierenarterien der linken und der rechten Niere unterschieden sich bezüglich ihrer Anatomie, jedoch nicht die Nierenarterienanatomie von Patienten mit kontrollierter und unkontrollierter Hypertonie. Die Diameter der Hauptnierenarterien waren bei Patienten mit eingeschränkter glomerulärer Filtrationsrate kleiner als bei nierengesunden Patienten. Sechs Monate nach renaler Denervation erfuhren Patienten mit kleinen Hauptnierenarterien (Diameter mindestens unilateral £4 mm) die größte Reduktion des 24-Stunden-Langzeitblutdrucks. Das Ausmaß der Blutdruckreduktion war unabhängig von der Länge der Nierenarterien und dem Vorliegen akzessorischer Nierenarterien oder einer renovaskulären Erkrankung.Background: Hypertension is highly prevalent and associated with cardiovascular morbidity and mortality. With increasing attention to renovascular causes and targets for hypertension arises a critical need for more detailed knowledge of renal arterial anatomy. However, a standardized nomenclature and morphometric data are lacking. The present study sought to develop a standardized nomenclature for renal anatomy considering the complexity and variation of the renal arterial tree and to assess the applicability of the nomenclature. Catheter-based renal sympathetic denervation has been introduced to lower sympathetic nerve activity and thereby blood pressure in patients with uncontrolled hypertension with mixed results. It has been postulated that anatomic and procedural elements introduce unaccounted variability and yet little is known of the impact of renal anatomy and procedural parameters on blood pressure response to renal denervation. Methods: A total of 1000 hypertensive patients underwent invasive selective renal artery angiography in nine centers in Europe and Australia. Further, 150 patients with resistant hypertension underwent bilateral renal denervation using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic) at Saarland University Medical Center in Homburg/Saar. Anatomical parameters were analyzed by quantitative vascular analysis and the prevalence of accessory renal arteries and renal artery disease were documented. Renal artery anatomy in 1000 patients with hypertension: Patient’s mean office blood pressure was 168/90±26/17 mmHg. As expected, the right main renal artery was longer than the left (41±15 versus 35±13 mm, p<0.001), but the left had a greater diameter (5.4±1.2 vs. 5.2±1.2 mm, p<0.001). Accessory renal arteries and renal artery disease were documented in 22% and 9% of the patients, respectively. Other than exhibiting a longer left main renal artery in uncontrolled hypertensives (+2.7 mm, p=0.034) there was no anatomical difference between patients with controlled and uncontrolled hypertension. Main renal artery mean diameter was smaller in patients with impaired kidney function (estimated glomerular filtration rate <90 ml/min, left -0.5 mm, right -0.4 mm, both p<0.001). Determinants of blood pressure lowering after renal denervation: Accessory renal arteries and renal artery disease were present in 56 (37%) and 14 patients (9%), respectively. At six months, 24-hour-ambulatory blood pressure was reduced by 11/6 mmHg (p<0.001 for both). Change of 24-hour-ambulatory systolic blood pressure was not related to the presence of accessory renal arteries (p=0.543) or renal artery disease (p=0.598). Patients with at least one main renal artery diameter £4 mm had a more pronounced reduction of 24-hour-ambulatory systolic blood pressure compared to patients where both arteries were >4mm (-19 versus -10 mmHg; p=0.038). Neither the length of the renal artery nor the number of radiofrequency ablations influenced 24- hour-ambulatory blood pressure reduction at six months. Conclusion: Renal arterial anatomy differs between sides but shows no difference between patients with and without blood pressure control. Impaired glomerular filtration rate was associated with small main renal artery diameter. Following renal denervation 24-hour-ambulatory blood pressure lowering was most pronounced in patients with smaller renal artery diameter but not related to renal artery length, accessory arteries or renal artery disease. Further, there was no dose-response relationship observed with increasing number of ablations

Urokinase versus Alteplase in Patients with Intermediate–High-Risk Pulmonary Embolism Treated with Ultrasound-Accelerated Endovascular Thrombolysis

Background. Ultrasound-accelerated thrombolysis (USAT) is a safe and effective treatment for patients with intermediate–high-risk pulmonary embolism (PE). In all studies investigating USAT in the setting of PE, the recombinant tissue-plasminogen activator (rt-PA) alteplase or actilyse was used. Currently, there is a shortage of alteplase (Alteplase, Boehringer Ingelheim) in Europe. It is unknown whether the efficacy of urokinase (UK) is comparable with alteplase for USAT in patients with PE. Methods. Patients with intermediate–high-risk PE undergoing USAT with urokinase and alteplase were included in this study. One-to-one nearest neighbour matching was performed to account for baseline differences. We identified one patient treated with USAT and UK (n = 9) for each patient treated with USAT and alteplase (n = 9). Results. A total of 56 patients underwent USAT. The treatment was successful in all patients. The propensity score matched the identified nine pairs of patients. There were no statistically significant differences in the change in right ventricle-to-left ventricle (RV/LV) ratio (0.4 ± 0.3 versus 0.5 ± 0.4, p = 0.54), systolic pulmonary artery pressure (17.3 ± 8.0 versus 18.1 ± 8.1, p = 0.17), or improvement of RV function (5.8 ± 3.8 versus 5.1 ± 2.6, p = 1.0). The complication rates were comparable (11% in both groups, p = 0.55). There were no deaths in hospital or during 90 days in either group. Conclusions. In this case-matched comparison, the short-term clinical and echocardiographic outcomes showed comparable results between USAT–UK and USAT–rt-PA

Hypertension trials update

Hypertension is one of the most prevalent cardiovascular diseases and its treatment requires multimodal therapeutic approaches. This review aims to provide a summary and update on relevant evidence in hypertension research published in 2019/2020. These include trials dealing with the prognostic effect of systolic and diastolic blood pressure values, the association between hypertension and valve disease, reproducibility of masked and white-coat hypertension, and the prognostic importance of ambulatory and night-time blood pressure measurements. Treatment of hypertension focusing on elderly patients but also the potential cancer risk of thiazide diuretics, the valsartan recall, chronotherapy, and device-based hypertension therapy are discussed

Assessing Adherence to Antihypertensive Medication by Means of Dose-Dependent Reference Plasma Concentration Ranges and Ultra-High Performance Liquid Chromatography-Ion Trap Mass Spectrometry Analysis

Poor adherence to antihypertensive drug therapy is a well-recognized problem and can be assessed by mass spectrometry-based analyses of body fluids. However, contrary statements exist whether drug quantification in blood or qualitative screening in urine is more suitable. The present pilot study aimed to further elucidate the power of blood plasma drug concentrations for adherence monitoring by developing and validating a quantification procedure for nine antihypertensive drugs (amlodipine, bisoprolol, candesartan, canrenone, carvedilol, metoprolol, olmesartan, torasemide, and valsartan) in blood plasma using liquid–liquid extraction and an ultra-high-performance liquid chromatography-ion trap mass spectrometry analysis. The procedure should then be used for an adherence assessment and compared with the results of an established qualitative urine screening. Selectivity, carryover, matrix effect, accuracy, precision, dilution integrity, and stability were successfully validated, except for amlodipine. The applicability was demonstrated by analyzing 19 plasma samples containing 28 antihypertensive drugs and comparing the measured concentrations with calculated dose-dependent reference plasma concentration ranges. The interpretation of plasma concentrations was found to be more sophisticated and time-consuming than that of urine screening results, and adherence could not be assessed in two cases (10%) due to measured plasma concentrations below the lower limit of quantification. However, 14 out of 19 subjects were classified as adherent (75%) and three as nonadherent (15%), in contrast to 19 (100%) that were claimed to be adherent based on the results of the qualitative urine screening. Nevertheless, further data is needed to estimate whether plasma quantification is superior in terms of assessing adherence to antihypertensive medication

Effects of non-uniform stiffness on the swimming performance of a passively-flexing, fish-like foil model

Author Posting. © The Author(s), 2015. This is the author's version of the work. It is posted here by permission of IOP Science for personal use, not for redistribution. The definitive version was published in Bioinspiration & Biomimetics 10 (2015): 056019, doi:10.1088/1748-3190/10/5/056019.Simple mechanical models emulating fish have been used recently to enable targeted study of individual factors contributing to swimming locomotion without the confounding complexity of the whole fish body. Yet, unlike these uniform models, the fish body is notable for its non-uniform material properties. In particular, flexural stiffness decreases along the fish’s anterior-posterior axis. To identify the role of non-uniform bending stiffness during fish-like propulsion, we studied four foil model configurations made by adhering layers of plastic sheets to produce discrete regions of high (5.5x10-5 Nm2) and low (1.9x10-5 Nm2) flexural stiffness of biologically-relevant magnitudes. This resulted in two uniform control foils and two foils with anterior regions of high stiffness and posterior regions of low stiffness. With a mechanical flapping foil controller, we measured forces and torques in three directions and quantified swimming performance under both heaving (no pitch) and constant 0o angle of attack programs. Foils self-propelled at Reynolds number 21,000-115,000 and Strouhal number ~0.20-0.25, values characteristic of fish locomotion. Although previous models have emphasized uniform distributions and heaving motions, the combination of non-uniform stiffness distributions and 0o angle of attack pitching program was better able to reproduce the kinematics of freely-swimming fish. This combination was likewise crucial in maximizing swimming performance and resulted in high self-propelled speeds at low costs of transport and large thrust coefficients at relatively high efficiency. Because these metrics were not all maximized together, selection of the “best” stiffness distribution will depend on actuation constraints and performance goals. These improved models enable more detailed, accurate analyses of fish-like swimming.This work was supported by an NSF Graduate Research Fellowship under grant DGE-1144152 to KNL and by ONR MURI Grant N000141410533 monitored by Dr Bob Brizzolara to GVL.2016-10-0

Effects of Arteriovenous Fistula on Blood Pressure in Patients With End-Stage Renal Disease: A Systematic Meta-Analysis

Background Central arteriovenous fistula ( AVF ) creation is under investigation for treatment of severe hypertension. We evaluated the effects of AVF for initiation of hemodialysis on systolic, diastolic, and mean arterial blood pressure in patients with end-stage renal disease. Methods and Results Data search included PubMed, Web of Science, and the Cochrane Library. A systematic review and meta-analysis of peer-reviewed studies reporting the effects of the creation/ligation of an AVF on blood pressure in patients with end-stage renal disease was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis), PRISMA -P (PRISMA for systematic review protocols), and ROBINS-I (Risk of Bias in Non-Randomized Studies) criteria by the Cochrane Bias Methods Group. All studies in which the results could have been biased by hemodialysis were excluded. A total of 14 trials including 412 patients with end-stage renal disease ( AVF creation, n=185; AVF ligation, n=227) fulfilled the criteria and were subsequently analyzed. Average blood pressure in patients with no/closed AVF was 140.5/77.6 mm Hg with a mean arterial blood pressure of 96.1 mm Hg. Following creation of AVF , systolic blood pressure significantly decreased by 8.7 mm Hg ( P<0.001), diastolic blood pressure by 5.9 mm Hg ( P<0.001), and mean arterial blood pressure by 6.6 mm Hg ( P=0.02), whereas after ligation systolic blood pressure increased by 5.2 mm Hg ( P=0.07), diastolic blood pressure by 3.8 mm Hg ( P=0.02), and mean arterial blood pressure by 3.7 mm Hg ( P=0.07) during short- to long-term follow-up. Conclusions Creation of AVF significantly decreases blood pressure in patients with end-stage renal disease, whereas blood pressure tends to increase after ligation. These findings illustrate the hemodynamic consequences of AVF which are under investigation for severe hypertension

Hidden sodium in effervescent-tablet dietary supplements and over-the-counter drugs: a comparative cross-sectional study

Objective Dietary sodium intake represents a risk factor for cardiovascular disease and mortality. The study sought to analyse the sodium content of effervescent dietary supplements and drugs in Germany and the USA. Design Comparative cross-sectional study. Setting and methods The sodium content of 39 dietary supplement effervescent tablets available in Germany was measured in May and June 2022 using optical emission spectrometry with inductively coupled argon plasma. The sodium content of 33 common pharmacy-only effervescent tablets (over-the-counter (OTC) drugs) in Germany was obtained from the summary of product characteristics. We compared the sodium content of the measured German dietary supplement effervescent tablets to that of 51 dietary supplement effervescent tablets available in the USA (data: National Institutes of Health’s Dietary Supplement Label Database). Results The measured sodium content in the German dietary supplements was 283.9±122.6 mg sodium/tablet, equivalent to 14±6% of the maximum recommended daily sodium intake (MRDSI). Vitamin products had the highest (378.3±112.8 mg, 19±6% of MRDSI), and calcium products had the lowest mean sodium content (170.4±113.2 mg, 9±6% of MRDSI). Vitamin products contained significantly more sodium than magnesium (378.3 mg vs 232.7 mg; p=0.004), calcium (378.3 mg vs 170.4 mg; p=0.006) and mineral products (378.3 mg vs 191.6 mg; p=0.048). The sodium content measured in products available in Germany was higher when compared with the declared sodium content on the label of the products sold in the USA (283.9 mg vs 190.0 mg; p<0.001). The median summary of product characteristics-declared sodium content of a single dose of the German OTC drugs was 157.0 mg (IQR: 98.9–417.3 mg); pain/common cold drugs contained the most sodium (median: 452.1 mg; IQR: 351.3–474.0 mg). Conclusion Effervescent tablets of nutritional supplements and OTC drugs contain high amounts of sodium, which often is not disclosed

Hidden sodium in effervescent-tablet dietary supplements and over-the-counter drugs: a comparative cross-sectional study

Objective Dietary sodium intake represents a risk factor for cardiovascular disease and mortality. The study sought to analyse the sodium content of effervescent dietary supplements and drugs in Germany and the USA. Design Comparative cross-sectional study. Setting and methods The sodium content of 39 dietary supplement effervescent tablets available in Germany was measured in May and June 2022 using optical emission spectrometry with inductively coupled argon plasma. The sodium content of 33 common pharmacyonly effervescent tablets (over-the-counter (OTC) drugs) in Germany was obtained from the summary of product characteristics. We compared the sodium content of the measured German dietary supplement effervescent tablets to that of 51 dietary supplement effervescent tablets available in the USA (data: National Institutes of Health’s Dietary Supplement Label Database). Results The measured sodium content in the German dietary supplements was 283.9±122.6 mg sodium/tablet, equivalent to 14±6% of the maximum recommended daily sodium intake (MRDSI). Vitamin products had the highest (378.3±112.8 mg, 19±6% of MRDSI), and calcium products had the lowest mean sodium content (170.4±113.2 mg, 9±6% of MRDSI). Vitamin products contained significantly more sodium than magnesium (378.3 mg vs 232.7 mg; p=0.004), calcium (378.3 mg vs 170.4 mg; p=0.006) and mineral products (378.3 mg vs 191.6 mg; p=0.048). The sodium content measured in products available in Germany was higher when compared with the declared sodium content on the label of the products sold in the USA (283.9 mg vs 190.0 mg; p<0.001). The median summary of product characteristics-declared sodium content of a single dose of the German OTC drugs was 157.0 mg (IQR: 98.9–417.3 mg); pain/common cold drugs contained the most sodium (median: 452.1 mg; IQR: 351.3–474.0 mg). Conclusion Effervescent tablets of nutritional supplements and OTC drugs contain high amounts of sodium, which often is not disclosed

Adherence to Antihypertensive Drugs Assessed by Hyphenated High-Resolution Mass Spectrometry Analysis of Oral Fluids

Background It is currently unknown if antihypertensive drugs can be monitored in oral fluid (OF) using liquid chromatography coupled to high-resolution mass spectrometry. Methods and Results We assessed adherence using liquid chromatography coupled to high-resolution mass spectrometry in OF, plasma, and urine of 56 consecutive patients with hypertension referred to a tertiary hypertension unit. Of these patients, 59% were completely adherent (all drugs detectable in urine), whereas 29% and 13% were partially adherent (1 drug not detectable in urine) or nonadherent (>1 drug not detectable in urine), respectively. Adherent patients were on fewer antihypertensive drugs (P=0.001), had fewer daily drug doses (P=0.012), and had lower 24-hour ambulatory systolic (P=0.012) and diastolic (P=0.009) blood pressures than nonadherent or partially adherent patients. Most drugs were detected in urine compared with plasma and OF (181 versus 119 versus 88; P=0.001). Compared with urine and plasma, detection rates of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics were lower in OF. There was no difference in the frequency of detecting β blockers (P=1.0) and calcium channel blockers (P=0.063) when comparing OF with urine. There was no difference in the number of calcium channel blockers (P=0.727), β blockers (P=1.000), thiazide diuretics (P=0.125), and α-2 agonists (P=0.125) identified between OF and plasma. Conclusions This study shows the feasibility of drug adherence testing for several antihypertensive drugs, especially those without acidic components, in OF, with a similar recovery compared with plasma. Therefore, drug adherence testing in OF should be further explored as a noninvasive approach, which can easily be performed in an "out-of-office" setting