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The current position of β-blockers in hypertension: guidelines and clinical practice.
Mahfoud, F, Wang, J, Ray, S
Current medical research and opinion. 2024;(sup1):25-32
Abstract
The benefits of improved clinical outcomes through blood pressure (BP) reduction have been proven in multiple clinical trials and meta-analyses. The new (2023) guideline from the European Society of Hypertension (ESH) includes β-blockers within five main classes of antihypertensive agents suitable for initiation of antihypertensive pharmacotherapy and for combination with other antihypertensive agents. This is in contrast to the 2018 edition of ESH guidelines that recommended β-blockers for use primarily in patients with compelling indications such as cardiovascular comorbidities, e.g. coronary heart disease, heart failure. This change was based on the fact that the magnitude of BP reduction is the most important factor for adverse cardiovascular outcomes, over and above the precise manner in which reduced BP is achieved. The ESH guideline also supports the use of β-blockers for patients with resting heart rate (>80 bpm); high resting heart rate is a sign of sympathetic overactivity, an important driver of adverse cardiac remodelling in the setting of hypertension and heart failure. Hypertension management guidelines support for the use of combination therapies for almost all patients with hypertension, ideally within a single-pill combination to optimise adherence to therapy. Where a β-blocker is prescribed, the inclusion of a dihydropyridine calcium channel blocker within a combination regimen is rational. These agents together reduce both peripheral and central BP, which epidemiological studies have shown is important for reducing the burden of premature morbidity and mortality associated with uncontrolled hypertension, especially strokes.
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Management of Resistant Hypertension.
Lauder, L, Mahfoud, F, Böhm, M
Annual review of medicine. 2024;:443-457
Abstract
Resistant hypertension (RH) is a severe form of hypertension associated with increased cardiovascular risk. Although true RH affects less than 10% of the patients receiving antihypertensive therapy, the absolute number is high and continues to increase. The workup of these patients requires screening for secondary hypertension and pseudoresistance, including poor adherence to prescribed medicines and the white-coat phenomenon. The treatment of RH consists of lifestyle modifications and pharmacological therapies. Lifestyle modifications include dietary adjustments, weight loss, physical activity, and limiting alcohol consumption; pharmacological therapies include diuretics, mineralocorticoid receptor antagonists, beta blockers, angiotensin receptor-neprilysin inhibitors, and others. Over the last 15 years, interventional approaches have emerged as adjunct treatment options; we highlight catheter-based renal denervation. This review summarizes the rationales and latest clinical evidence and, based thereon, proposes an updated algorithm for the management of RH.
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Empagliflozin, irrespective of blood pressure, improves outcomes in heart failure with preserved ejection fraction: the EMPEROR-Preserved trial.
Bhm, M, Anker, S, Mahfoud, F, Lauder, L, Filippatos, G, Ferreira, JP, Pocock, SJ, Brueckmann, M, Saloustros, I, Schler, E, et al
European heart journal. 2023;(5):396-407
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Abstract
AIMS: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and preserved ejection fraction. This study aims to evaluate if systolic blood pressure (SBP) moderates these effects. METHODS AND RESULTS The association of SBP and the treatment effects of empagliflozin in EMPEROR-Preserved (empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction) was evaluated. Randomized patients (n 5988) were grouped according to SBP at baseline (110 mmHg, n 455; 110130 mmHg, n 2415; 130 mmHg, n 3118). The effect of empagliflozin on blood pressure, cardiovascular death or HF hospitalization (primary outcome), total HF hospitalizations, and rate of decline in estimated glomerular filtration rate was studied. Over a median of 26.2 months, the placebo-corrected decline was small and not significantly different across baseline SBP. On placebo, the risk of cardiovascular death or hospitalization for HF was 8.58 at 130 mmHg, 8.26 at 110130 mmHg, and 11.59 events per 100 patient-years at 110 mmHg (P 0.12 vs. 130 mmHg, P 0.08 vs. 110130 mmHg). There was no evidence for baseline SBP moderating the effect of empagliflozin on risk of HF events (primary endpoint interaction P 0.69, recurrent HF hospitalizations interaction P 0.55). When comparing empagliflozin with placebo, SBP did not meaningfully associate with adverse events such as hypotension, volume depletion, and acute renal failure. CONCLUSION In EMPEROR-Preserved, empagliflozin was effective and safe without SBP meaningfully moderating empagliflozins treatment effects. This analysis of EMPEROR-Preserved shows that empagliflozin can be used safely and effectively without blood pressure being a meaningful moderator of the drug benefit. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov Unique identifier: NCT03057951.
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Hidden sodium in effervescent-tablet dietary supplements and over-the-counter drugs: a comparative cross-sectional study.
Kunz, M, Götzinger, F, Jacobs, CM, Lauder, L, Ukena, C, Meyer, MR, Laufs, U, Schulz, M, Böhm, M, Mahfoud, F
BMJ open. 2023;(11):e076302
Abstract
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.
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Closing the gap - development of an analytical methodology using volumetric absorptive microsampling of finger prick blood followed by LC-HRMS/MS for adherence monitoring of antihypertensive drugs.
Jacobs, CM, Kunz, M, Mahfoud, F, Wagmann, L, Meyer, MR
Analytical and bioanalytical chemistry. 2023;(1):167-177
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Abstract
Volumetric absorptive microsampling (VAMS), an emerging microsampling technique, is a promising tool for adherence monitoring. This study focused on development of an analytical methodology to improve VAMS-based strategies for adherence assessment by analyzing angiotensin-converting-enzyme (ACE) inhibitors, loop diuretics, a potassium-sparing diuretic, and a thiazide diuretic. Development included sample preparation, chromatographic conditions, mass spectrometry settings, validation, and demonstrating proof of concept. Quantification of analytes, by name furosemide, hydrochlorothiazide, lisinopril, torasemide, and the active metabolites, canrenone, enalaprilat, and ramiprilat in finger prick blood (FPB), was validated based on international guidelines. Selectivity, carryover, and within/between-run accuracy and precision were in accordance with the recommendations. The matrix effect was evaluated at three different hematocrit levels (HT: 20%, 40%, 60%) and the coefficients of variation did not exceed 15%. Dilution integrity (1:10 and 1:20) was given for all analytes except lisinopril, yet for lisinopril, the therapeutic range was already covered by the calibration range. Long-term stability in VAMS tips was tested for 2 weeks at 24 °C in the dark and revealed no degradation of analytes. The proof of concept was performed by analyzing 35 intakes of ACE-inhibitors and diuretics in 18 VAMS and matched plasma samples. Hereby, determined concentration in FPB and plasma cannot be used interchangeably, and thus specific reference ranges for whole blood must be established. Nevertheless, the VAMS-based strategy was shown to be suitable for assessing adherence of all classes of antihypertensive drugs used in the guidelines to manage hypertension.
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2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA).
Mancia, G, Kreutz, R, Brunström, M, Burnier, M, Grassi, G, Januszewicz, A, Muiesan, ML, Tsioufis, K, Agabiti-Rosei, E, Algharably, EAE, et al
Journal of hypertension. 2023;(12):1874-2071
Abstract
Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).
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Hypertension management in patients with cardiovascular comorbidities.
Lauder, L, Mahfoud, F, Azizi, M, Bhatt, DL, Ewen, S, Kario, K, Parati, G, Rossignol, P, Schlaich, MP, Teo, KK, et al
European heart journal. 2023;(23):2066-2077
Abstract
Arterial hypertension is a leading cause of death globally. Due to ageing, the rising incidence of obesity, and socioeconomic and environmental changes, its incidence increases worldwide. Hypertension commonly coexists with Type 2 diabetes, obesity, dyslipidaemia, sedentary lifestyle, and smoking leading to risk amplification. Blood pressure lowering by lifestyle modifications and antihypertensive drugs reduce cardiovascular (CV) morbidity and mortality. Guidelines recommend dual- and triple-combination therapies using renin-angiotensin system blockers, calcium channel blockers, and/or a diuretic. Comorbidities often complicate management. New drugs such as angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists improve CV and renal outcomes. Catheter-based renal denervation could offer an alternative treatment option in comorbid hypertension associated with increased sympathetic nerve activity. This review summarises the latest clinical evidence for managing hypertension with CV comorbidities.
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Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk.
Böhm, M, Schumacher, H, Werner, C, Teo, KK, Lonn, EM, Mahfoud, F, Speer, T, Mancia, G, Redon, J, Schmieder, RE, et al
Cardiovascular diabetology. 2022;(1):12
Abstract
BACKGROUND Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. METHODS Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. RESULTS Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097-0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). CONCLUSIONS Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov.uniqueidentifier :NCT00153101.
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Photoinduced skin reactions of cardiovascular drugs-a systematic review.
Götzinger, F, Reichrath, J, Millenaar, D, Lauder, L, Meyer, MR, Böhm, M, Mahfoud, F
European heart journal. Cardiovascular pharmacotherapy. 2022;(4):420-430
Abstract
This systemic review aims to provide a practical overview of the prevalence, clinical manifestation, and management of adverse photoinduced skin reactions caused by frequently used cardiovascular drugs and to assess their potential relevance for skin cancer development. Data search included PubMed, Web of Science, and the Cochrane Library. A systematic review of peer-reviewed studies reporting the photosensitizing and/or skin cancer-inducing properties of common cardiovascular drugs was performed and a guide to clinical management of photoinduced skin eruptions by cardiovascular drugs was provided. Study quality was assessed for major methodological biases. A total of 58 studies were identified (i.e. 23 case reports, 14 observational studies, 10 review articles, 10 experimental studies, and 1 meta-analysis). Most commonly, drug-associated adverse photoinduced cutaneous reactions were caused by phototoxic and photoallergic mechanisms. There is evidence suggesting that amiodarone and dronedarone, thiazide diuretics, thiazide-like diuretics, angiotensin receptor blockers, dihydropyridine-type calcium channel blockers, and certain angiotensin-converting enzyme inhibitors and statins may cause photoinduced adverse cutaneous reactions. Other drugs such as anticoagulants, antiplatelets, aldosterone antagonists, and fibrates have not been linked with photosensitizing reactions or adverse cutaneous reactions. Some drugs, i.e. thiazides and thiazide-like diuretics, were associated with an increased risk of non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma). Certain commonly used cardiovascular drugs have been associated with adverse photoinduced cutaneous reactions. If they occur, further diagnosis and treatment might be needed, depending on the severity and progress. Whether photosensitizing drugs increase the risk of skin cancer remains elusive and further randomized controlled trials are required.
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Arterial hypertension - clinical trials update 2022.
Götzinger, F, Kunz, M, Lauder, L, Böhm, M, Mahfoud, F
Hypertension research : official journal of the Japanese Society of Hypertension. 2022;(7):1140-1146
Abstract
Hypertension is the most prevalent cardiovascular risk factor worldwide and is associated with increased cardiovascular morbidity and mortality. Despite the availability of multimodal therapeutic approaches, a large number of patients do not achieve guideline-recommended blood pressure targets, which reiterates the importance of continued research in the field. This article summarizes and discusses the most relevant clinical trials in hypertension research published in 2021 and 2022. The topics include new insights into treatment targets in the elderly, novel findings of salt consumption and lifestyle interventions in resistant hypertension, new evidence about early antihypertensive combination therapy and the use of angiotensin II receptor blocker neprilysin inhibitors in resistant hypertension, as well as data regarding the safety of antihypertensive drugs with respect to cancerogeneity and regarding the impact of acetaminophen, a commonly used pain medication, on blood pressure. Finally, we provide an update on recent evidence on renal denervation and its role in current hypertension management.