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1
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Tabrizchi R. Management of drug-resistant hypertension as a heterogeneous disorder. Pharmacol Ther 2025; 271:108875. [PMID: 40339756 DOI: 10.1016/j.pharmthera.2025.108875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/09/2025] [Accepted: 04/21/2025] [Indexed: 05/10/2025]
Abstract
Approximately 1.3 billion adults globally have hypertension, and are at higher risk of death associated with cardiovascular disease. Adjusted death rate primarily due to high blood pressure is 31.3 per 100,000. The prevalence of drug-resistant hypertension is estimated to be up to 20 % in hypertensive individuals, and is more common in those with chronic kidney disease and obstructive sleep apnea. It occurs in individuals on ≥3 antihypertensive drugs including a diuretic. The addition of spironolactone, as a fourth drug has been found at times to be effective in management of blood pressure. Other strategies include sequential nephron block (e.g., spironolactone + furosemide + amiloride), and use of drugs such as alpha2 agonists, endothelin antagonists, and nonsteroidal mineralocorticoid antagonists. Use of positive airway pressure and pharmacotherapy have been found to be of value in individuals with sleep apnea in lowering blood pressure. In contrast, baroreceptor stimulation and/or renal denervation combined with pharmacotherapy seem to offer little in a way of consistent efficacy of optimally lowering blood pressures. Remarkably, evidence in the literature strongly supports the view that life style changes including regular exercise and appropriate diet combined with pharmacotherapy can lead to positive outcomes in helping to significantly reduce blood pressure. There is also ample data in literature suggesting the non-compliance to antihypertensive medications as a significant barrier to lowering blood pressure in this group. Accordingly, education regarding pharmacotherapy, and appropriate exercise regimen, including changes to diet should underpin any strategy in the management of high blood pressure in this population.
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Affiliation(s)
- Reza Tabrizchi
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
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2
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Fisher NDL, Kirtane AJ. Renal denervation for hypertension. Nat Rev Cardiol 2025:10.1038/s41569-024-01104-z. [PMID: 39743561 DOI: 10.1038/s41569-024-01104-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/30/2024] [Indexed: 01/04/2025]
Abstract
Innovative therapies for hypertension are desperately needed given the rising prevalence and falling rates of control of hypertension despite an abundance of available medical therapies. Procedural interventions lower blood pressure without depending on adherence to medications, and endovascular renal denervation (RDN) is the interventional procedure with the best evidence base for the treatment of hypertension. After nearly two decades of study, with major refinements to devices, technique and trial design, two different systems for RDN received approval from the FDA in late 2023 for the treatment of hypertension. These decisions were based on a portfolio of sham-controlled clinical trials demonstrating efficacy and safety of both radiofrequency and ultrasound RDN in treating patients across the spectrum of hypertension, including patients with mild disease taking no or one medication as well as those with moderate and truly resistant hypertension. In this Review, we begin by summarizing the background and scope of the global problem of hypertension control and explore the evolution and mechanism of RDN. We then detail early studies and randomized clinical trials demonstrating the efficacy and safety of RDN procedures, review international statements, and provide practical guidance on patient selection and implementation of RDN, including the crucial aspects of building a hypertension team and of involving patients in shared decision-making.
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Affiliation(s)
- Naomi D L Fisher
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - Ajay J Kirtane
- Division of Cardiology, Columbia University Irving Medical Center, New York, NY, USA
- New York-Presbyterian Hospital, New York, NY, USA
- Cardiovascular Research Foundation, New York, NY, USA
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3
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Faconti L, George J, Partridge S, Maniero C, Sathyanarayanan A, Kulkarni S, Kapil V, Petrosino A, Lewis P, McCormack T, Poulter NR, Heagerty A, Wilkinson IB. Investigation and management of resistant hypertension: British and Irish Hypertension Society position statement. J Hum Hypertens 2025; 39:1-14. [PMID: 39653728 PMCID: PMC11717708 DOI: 10.1038/s41371-024-00983-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/15/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025]
Abstract
People living with resistant hypertension (RH) are at high risk of adverse cardiovascular events. The British and Irish Hypertension Society has identified suspected RH as a condition for which specialist guidance may improve rates of blood pressure control and help clinicians identify those individuals who may benefit from specialist review. In this position statement we provide a practical approach for the investigation and management of adults with RH. We highlight gaps in the current evidence and identify important future research questions. Our aim is to support the delivery of high-quality and consistent care to people living with RH across the UK and Ireland.
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Affiliation(s)
- Luca Faconti
- Department of Clinical Pharmacology, King's College London British Heart Foundation Centre, St. Thomas' Hospital, London, UK.
| | - Jacob George
- Division of Molecular & Clinical Medicine, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK
| | - Sarah Partridge
- Department of Primary Care and Public Health, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Carmen Maniero
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | | | - Spoorthy Kulkarni
- Division of Experimental Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Vikas Kapil
- William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
- Barts Blood Pressure Centre of Excellence, Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK
| | - Alfredo Petrosino
- London Tubular Centre, Department of Renal Medicine, University College London, Royal Free Hospital, London, UK
| | | | - Terry McCormack
- Institute of Clinical and Applied Health Research, Hull York Medical School, Hull, UK
| | - Neil R Poulter
- Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, UK
| | - Anthony Heagerty
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Ian B Wilkinson
- Division of Experimental Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
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Rabbitt L, Curneen J, Dennedy MC, Molloy GJ. Chemical adherence testing in the clinical management of hypertension: a scoping review. Front Pharmacol 2024; 15:1452464. [PMID: 39568584 PMCID: PMC11576289 DOI: 10.3389/fphar.2024.1452464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/18/2024] [Indexed: 11/22/2024] Open
Abstract
Background Despite growing use, questions remain surrounding the utility, acceptability and feasibility of chemical adherence testing (CAT) as part of hypertension management in clinical practice. Objectives This scoping review aimed to (i) identify and summarise studies using CAT in hypertension management, and (ii) describe and critically evaluate how CAT is currently being used in the clinical management of hypertension. Eligibility criteria Peer-reviewed and published studies in English, reporting original research in any setting, with any study design, were included. Search concepts included hypertension, medication adherence, CAT, and their synonyms. Sources of evidence Searches were carried out using Ovid Medline, EMBASE, and PsycInfo (EBSCO), alongside manual searching of reference lists. Using Covidence software, we screened titles and abstracts, followed by full-text articles. Data from the included articles were tabulated and summarised. Results Of the 618 studies identified, 48 were included. The studies cover diverse clinical settings, and were mostly observational in design. 7 studies reporting adherence analyses within clinical trials for hypertension therapies. The use of theoretical frameworks to guide reporting was rare, and there was considerable variation in key terminology and definitions, most notably in the definition of adherence. Conclusion The current body of evidence demonstrates considerable variability in the approach to implementing CAT for hypertension management in clinical practice, and a paucity of randomised controlled trials to evaluate its impact. Future research could (i) adopt a cohesive theoretical framework including clear operational definitions to standardise the approach to this important topic; (ii) further explore the impact of CAT on clinical outcomes using RCTs.
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Affiliation(s)
- Louise Rabbitt
- Department of Pharmacology, School of Medicine, University of Galway, Galway, Ireland
- Galway University Hospital, Saolta Healthcare Group, Galway, Ireland
| | - James Curneen
- Department of Pharmacology, School of Medicine, University of Galway, Galway, Ireland
- Galway University Hospital, Saolta Healthcare Group, Galway, Ireland
| | - Michael Conall Dennedy
- Department of Pharmacology, School of Medicine, University of Galway, Galway, Ireland
- Galway University Hospital, Saolta Healthcare Group, Galway, Ireland
| | - Gerard J. Molloy
- Galway University Hospital, Saolta Healthcare Group, Galway, Ireland
- School of Psychology, University of Galway, Galway, Ireland
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Gebremariam SN, Sema FD, Jara AG, Mekonnen GA. Medication-Related Hospital Admission Among Patients Admitted to the Emergency Ward at the University of Gondar, North West Ethiopia: A Cross Sectional Study. Drug Healthc Patient Saf 2024; 16:75-88. [PMID: 39050408 PMCID: PMC11268659 DOI: 10.2147/dhps.s455990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/27/2024] [Indexed: 07/27/2024] Open
Abstract
Background Medication-related hospital admission (MRHA) is hospitalization due to drug-related problems. MRHAs have been reported to be on the rise in recent decades. Objective This study was aimed at determining the prevalence, patterns, and predictors of MRHA among patients visiting the emergency ward of the University of Gondar comprehensive specialized hospital, Ethiopia. Methods A cross-sectional study was conducted from June 1, 2022, to August 30, 2022 G.C. in the emergency ward at the University of Gondar Comprehensive Specialized Hospital. The AT-HARM 10 tool was used to collect data from participants who fulfilled the inclusion criteria. Data was entered into EpiData Manager 4.6.0.0 and was exported to Statistical Package for Social Sciences (SPSS) version 24 for analysis. Descriptive statistics were presented using frequency and percentage. Binary logistic regression was applied to identify factors associated with MRHAs with a 95% confidence level, and significance was declared at a p-value <0.05. Results The prevalence of MRHAs was 30.5% (95% CI = 27.7-36.4%). More than half (64.52%) of MRHAs were definitely preventable. The majority of MRHAs (48.39%) were severe. Non-compliance (41.12%), followed by untreated indication (26.61%) and adverse drug reaction (12.09%) were the most frequent causes of MRHAs. Renal impairment (AOR = 2.703, 95% CI: 1.29 to 5.663), chronic disease (AOR = 10.95, 95% CI: 4.691 to 25.559), history of traditional medication use (AOR = 2.089, 95% CI: 1.162 to 3.755), and history of hospitalization (AOR = 4.001, 95% CI: 1.98 to 8.089) were significantly associated with MRHAs. Conclusion MRHAs were substantially prevalent. Most of the MRHAs were definitely preventable. Renal impairment, chronic disease, history of traditional medication use, and history of hospitalization were predictors of MRHAs. At the university hospital, health care providers should strive to prevent and manage MRHAs appropriately.
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Affiliation(s)
- Saron Naji Gebremariam
- Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Faisel Dula Sema
- Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Abdisa Gemedi Jara
- Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Gizework Alemnew Mekonnen
- Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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6
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Schiffrin EL, Fisher NDL. Diagnosis and management of resistant hypertension. BMJ 2024; 385:e079108. [PMID: 38897628 DOI: 10.1136/bmj-2023-079108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Resistant hypertension is defined as blood pressure that remains above the therapeutic goal despite concurrent use of at least three antihypertensive agents of different classes, including a diuretic, with all agents administered at maximum or maximally tolerated doses. Resistant hypertension is also diagnosed if blood pressure control requires four or more antihypertensive drugs. Assessment requires the exclusion of apparent treatment resistant hypertension, which is most often the result of non-adherence to treatment. Resistant hypertension is associated with major cardiovascular events in the short and long term, including heart failure, ischemic heart disease, stroke, and renal failure. Guidelines from several professional organizations recommend lifestyle modification and antihypertensive drugs. Medications typically include an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, a calcium channel blocker, and a long acting thiazide-type/like diuretic; if a fourth drug is needed, evidence supports addition of a mineralocorticoid receptor antagonist. After a long pause since 2007 when the last antihypertensive class was approved, several novel agents are now under active development. Some of these may provide potent blood pressure lowering in broad groups of patients, such as aldosterone synthase inhibitors and dual endothelin receptor antagonists, whereas others may provide benefit by allowing treatment of resistant hypertension in special populations, such as non-steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease. Several device based approaches have been tested, with renal denervation being the best supported and only approved interventional device treatment for resistant hypertension.
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Affiliation(s)
- Ernesto L Schiffrin
- Lady Davis Institute for Medical Research and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, QC, Canada
| | - Naomi D L Fisher
- Department of Medicine, Brigham and Women's Hospital, Harvard University, Boston, MA, USA
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Pilkova A, Sima M, Hartinger JM, Nikrynova Nguyen TMP, Maresova V, Kurcova I, Slanar O, Widimsky J. Novel approach to adherence assessment based on parent drug and metabolite pharmacokinetics: pilot study with spironolactone. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2024; 168:117-123. [PMID: 36472169 DOI: 10.5507/bp.2022.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022] Open
Abstract
AIM The aim of this study was to evaluate adherence to spironolactone in a group of unselected patients with arterial hypertension by analysis of measured serum spironolactone and canrenone concentrations according to a proposed two-step decision scheme based on pharmacokinetic considerations. MATERIALS AND METHODS Simulation of serum concentration-time profiles of spironolactone and canrenone based on population pharmacokinetic parameters described in literature and a body weight-normalized spironolactone dose / canrenone level nomogram derived from a group of adherent patients with conservatively treated primary hyperaldosteronism, were used to create a two-step decision scheme. 71 outpatients treated with spironolactone for resistant hypertension with spironolactone and canrenone serum concentrations measured between 2018 and 2021 were analyzed according to the proposed scheme. We compared our proposed methodology to the standard approach for adherence testing. RESULTS With the most sensitive traditional approach to adherence assessment through detectable serum concentrations of spironolactone and/or canrenone, 9 (12.7%) non-adherent patients were identified. With our two-step assessment of adherence, we were able to identify 18 (25.4%) non-adherent patients. CONCLUSION Consideration of the pharmacokinetic properties of parental drug and its metabolite led to improved sensitivity in non-adherence detection in patients with arterial hypertension. This approach enables better interpretation of measured spironolactone and canrenone serum concentrations and should be used in clinical practice.
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Affiliation(s)
- Alena Pilkova
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Martin Sima
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Jan Miroslav Hartinger
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Thi Minh Phuong Nikrynova Nguyen
- Third Internal Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Vera Maresova
- Institute of Forensic Medicine and Toxicology, Toxicology Laboratory, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Ivana Kurcova
- Institute of Forensic Medicine and Toxicology, Toxicology Laboratory, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Ondrej Slanar
- Department of Clinical Pharmacology and Pharmacy, Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Jiri Widimsky
- Third Internal Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
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8
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Parodi R, Brandani L, Romero C, Klein M. Resistant hypertension: Diagnosis, evaluation, and treatment practical approach. Eur J Intern Med 2024; 123:23-28. [PMID: 38228447 DOI: 10.1016/j.ejim.2023.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 12/24/2023] [Accepted: 12/29/2023] [Indexed: 01/18/2024]
Abstract
The term RH describes a subgroup of hypertensive patients whose BP is uncontrolled despite the use of at least three antihypertensive drugs in an appropriate combination at optimal or best tolerated doses. True RH is considered when appropriate lifestyle measures and treatment with optimal or best tolerated doses of three or more drugs (a thiazide/thiazide-like diuretic, plus renin-angiotensin system -RAS- blocker and a calcium channel blocker -CCB-) fail to lower office BP to <140/90 mmHg; besides the inadequate BP control should be confirmed by home blood pressure monitoring (HBPM) or 24-hour ambulatory; and evidence of adherence to therapy and exclusion of secondary causes of hypertension are required. RH patients are at a high risk of cardiovascular events and death. RH is associated with a higher prevalence of end-organ damage. When stricter criteria are applied, a reasonable estimate of the prevalence of true RH is 5 % of the total hypertensive population. The predominant hemodynamic pattern appears to be increased systemic vascular resistance and plasma volume with normal or even low cardiac output. We must rule out pseudo-resistance before diagnosing true drug resistance. RH is a therapeutic challenge, and its management includes lifestyle interventions, avoiding nonadherence to treatment, avoiding inertia, appropriate use of antihypertensive drugs based on current evidence, especially long-acting diuretics, and the addition of mineralocorticoid receptor antagonists. RCTs to identify the most protective medical therapy in RH are needed. A series of drugs in different stages of investigation could significantly impact RH treatment in the future.
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Affiliation(s)
- Roberto Parodi
- Rosario National University, Hospital Provincial del Centenario, Rosario, Argentina.
| | - Laura Brandani
- Favaloro Foundation University Hospital, Buenos Aires, Buenos Aires, Argentina
| | - César Romero
- Renal Division, Emory University School of Medicine, Atlanta, GA, USA
| | - Manuel Klein
- Argentina Society of Medicine, Buenos Aires, Argentina
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Fadl Elmula FEM, Mariampillai JE, Heimark S, Kjeldsen SE, Burnier M. Medical Measures in Hypertensives Considered Resistant. Am J Hypertens 2024; 37:307-317. [PMID: 38124494 PMCID: PMC11016838 DOI: 10.1093/ajh/hpad118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Patients with resistant hypertension are the group of hypertensive patients with the highest cardiovascular risk. METHODS All rules and guidelines for treatment of hypertension should be followed strictly to obtain blood pressure (BP) control in resistant hypertension. The mainstay of treatment of hypertension, also for resistant hypertension, is pharmacological treatment, which should be tailored to each patient's specific phenotype. Therefore, it is pivotal to assess nonadherence to pharmacological treatment as this remains the most challenging problem to investigate and manage in the setting of resistant hypertension. RESULTS Once adherence has been confirmed, patients must be thoroughly worked-up for secondary causes of hypertension. Until such possible specific causes have been clarified, the diagnosis is apparent treatment-resistant hypertension (TRH). Surprisingly few patients remain with true TRH when the various secondary causes and adherence problems have been detected and resolved. Refractory hypertension is a term used to characterize the treatment resistance in hypertensive patients using ≥5 antihypertensive drugs. All pressor mechanisms may then need blockage before their BPs are reasonably controlled. CONCLUSIONS Patients with resistant hypertension need careful and sustained follow-up and review of their medications and dosages at each term since medication adherence is a very dynamic process.
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Affiliation(s)
- Fadl Elmula M Fadl Elmula
- Division of Medicine, Ullevaal University Hospital, Cardiorenal Research Centre, Oslo, Norway
- Heart Center, King Faisal Specialist Hospital and Research Center, Riyadh, KSA
| | | | - Sondre Heimark
- Division of Medicine, Ullevaal University Hospital, Cardiorenal Research Centre, Oslo, Norway
- Medical Faculty, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Nephrology, Ullevaal University Hospital, Oslo, Norway
| | - Sverre E Kjeldsen
- Division of Medicine, Ullevaal University Hospital, Cardiorenal Research Centre, Oslo, Norway
- Medical Faculty, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Cardiology, Ullevaal University Hospital, Oslo, Norway
| | - Michel Burnier
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
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10
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Schiffrin EL. RNA Injection Every 6 Months to Improve Adherence and Lower Blood Pressure in Patients With Hypertension. JAMA 2024; 331:733-735. [PMID: 38363578 DOI: 10.1001/jama.2023.26071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Affiliation(s)
- Ernesto L Schiffrin
- Lady Davis Institute for Medical Research, and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec, Canada
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11
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Filippone EJ, Naccarelli GV, Foy AJ. Controversies in Hypertension V: Resistant and Refractory Hypertension. Am J Med 2024; 137:12-22. [PMID: 37832756 DOI: 10.1016/j.amjmed.2023.09.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023]
Abstract
Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15% of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regimen, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by volume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated. The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (α-β blockade, centrally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit for resistance, but its role in refractory hypertension remains to be defined.
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Affiliation(s)
- Edward J Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pa.
| | - Gerald V Naccarelli
- Department of Medicine, Penn State University Heart and Vascular Institute, Penn State M.S. Hershey Medical Center and College of Medicine, Hershey, Pa
| | - Andrew J Foy
- Department of Medicine, Penn State University Heart and Vascular Institute, Penn State M.S. Hershey Medical Center and College of Medicine, Hershey, Pa
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12
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Kiuchi MG, Carnagarin R, Schultz C, Shetty S, Ward NC, Santos CE, Schlaich MP. Update on advanced interventional neuromodulatory approaches to lower blood pressure. Heart 2023; 109:1734-1740. [PMID: 37353317 DOI: 10.1136/heartjnl-2022-321499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 06/01/2023] [Indexed: 06/25/2023] Open
Abstract
Herein, we review interventional peripheral neuromodulatory approaches to reduce blood pressure (BP), specifically focusing on catheter-based renal denervation (RDN), as well as the latest data from recent clinical trials underpinning its clinical use. Given the apparent failure of established lifestyle measures and pharmacologic BP-lowering approaches to improve hypertension (HTN) control rates, the past decade has seen remarkable scientific efforts to explore the utility of interventional strategies for BP management. Experimental studies and human clinical trials have demonstrated the crucial role of the sympathetic nervous system in the development and mainenance of HTN - consequently, most recent interventional technologies aimed primarily at modulating neural pathways. Advanced approaches that were rigorously tested in human studies include RDN, endovascular baroreflex amplification, baroreflex activation therapy and cardiac neuromodulation stimulation.Amongst these, RDN is by far the most established technology. With recent robust evidence from clinical trials and real-world data showing the safety and efficacy of both ultrasound and radiofrequency-based approaches, a recent clinical consensus statement of the European Society of Cardiology Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions concludes that RDN represents an ancillary therapeutic option in patients with uncontrolled resistant HTN confirmed by ambulatory blood pressure measurement and in spite of attention to lifestyle changes and optimised pharmacological treatment. Furthermore, RDN could alos be considered for patienst unlikley to adhere to or tolerate long-term antihypertensive drug treatment. Very recent data indicate long-term safety and efficacy up to 10 years. Appropriate implementation of RDN into clinical practice is now warranted.For all other interventions additional data from adequately designed human studies are required to establish their safety and clinical utility for potential future use in routine practice.
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Affiliation(s)
- Marcio Galindo Kiuchi
- Dobney Hypertension Centre, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Revathy Carnagarin
- Dobney Hypertension Centre, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Carl Schultz
- Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - Sharad Shetty
- Department of Cardiology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - Natalie C Ward
- Dobney Hypertension Centre, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | | | - Markus P Schlaich
- Dobney Hypertension Centre, Medical School, The University of Western Australia, Perth, Western Australia, Australia
- Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia
- Department of Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia
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13
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Kociánová E, Táborský M, Václavik J. A practical approach to assessment of non-adherence to antihypertensive treatment. J Hypertens 2023; 41:1371-1375. [PMID: 37345493 DOI: 10.1097/hjh.0000000000003492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2023]
Abstract
Non-adherence to antihypertensive treatment is frequent, complicates the care of hypertensive patients, represents one of the major causes of treatment failure and is linked with the increased risk of cardiovascular events. Identifying a non-adherent patient is one of the recent daily-practice tasks for which the ideal solution has not yet been found. Presence of certain clinical red flags should prompt the clinician to consider non-adherence. Chemical adherence testing using serum or urine antihypertensive levels is regarded as the best method so far and should be used if available. Alternatively, the check for prescription refills in the patient electronic medical records, or directly observed therapy with subsequent ambulatory blood pressure monitoring may be used. We suggest a simple algorithm to guide the clinicians to detect non-adherence in the practice.
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Affiliation(s)
- Eva Kociánová
- First Department of Internal Medicine - Cardiology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc
| | - Miloš Táborský
- First Department of Internal Medicine - Cardiology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc
| | - Jan Václavik
- University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
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14
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Sharma JR, Dludla PV, Dwivedi G, Johnson R. Measurement Tools and Utility of Hair Analysis for Screening Adherence to Antihypertensive Medication. Glob Heart 2023; 18:17. [PMID: 36968302 PMCID: PMC10038111 DOI: 10.5334/gh.1191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 02/16/2023] [Indexed: 03/29/2023] Open
Abstract
Poor adherence to the prescribed antihypertensive therapy is an understated public health problem and is one of the main causes of the high prevalence of uncontrolled hypertension in sub-Saharan Africa. Medication adherence is vital for the effectiveness of antihypertensive treatment and is key to ameliorating the clinical outcomes in hypertensive patients. However, it has often been ignored because the current methods used to assess medication adherence are not reliable, limiting their utilization in clinical practice. Therefore, the identification of the most accurate and clinically feasible method for measuring medication adherence is critical for tailoring effective strategies to improve medication adherence and consequently achieve blood pressure goals. This review not only explores various available methods for estimating medication adherence but also proposes therapeutic drug monitoring in hair for the measurement of medication adherence to the antihypertensive medication period.
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Affiliation(s)
- Jyoti R. Sharma
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Phiwayinkosi V. Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Girish Dwivedi
- Medical School, University of Western Australia, Harry Perkins Institute of Medical Sciences, Fiona Stanley Hospital, Verdun Street, Nedlands WA, 6009, Australia
| | - Rabia Johnson
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
- Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa
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15
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Adams D, Tournev IL, Taylor MS, Coelho T, Planté-Bordeneuve V, Berk JL, González-Duarte A, Gillmore JD, Low SC, Sekijima Y, Obici L, Chen C, Badri P, Arum SM, Vest J, Polydefkis M. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid 2023; 30:1-9. [PMID: 35875890 DOI: 10.1080/13506129.2022.2091985] [Citation(s) in RCA: 158] [Impact Index Per Article: 79.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/18/2022] [Accepted: 06/16/2022] [Indexed: 11/01/2022]
Abstract
BACKGROUND The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. METHODS HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. RESULTS HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10-12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. CONCLUSIONS Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile. CLINICALTRIALS.GOV NCT03759379.
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Affiliation(s)
- David Adams
- Neurology Department, CHU Bicêtre, APHP, Université Paris-Saclay, Le Kremlin Bicêtre Cedex, France
| | - Ivailo L Tournev
- Department of Neurology, Clinic of Nervous Diseases, University Hospital Aleksandrovska, Medical University, Sofia, Bulgaria
- Department of Cognitive Sciences, New Bulgarian University, Sofia, Bulgaria
| | - Mark S Taylor
- Department of Clinical Immunology and Allergy, Westmead Hospital and Westmead Clinical School, University of Sydney, Sydney, NSW, Australia
| | - Teresa Coelho
- Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | | | - John L Berk
- Boston Medical Center, Boston University, Boston, Massachusetts, USA
| | | | - Julian D Gillmore
- National Amyloidosis Centre, University College London, Royal Free Hospital, London, UK
| | - Soon-Chai Low
- Department of Medicine, Division of Neurology, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Yoshiki Sekijima
- Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
| | - Laura Obici
- Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
| | - Chongshu Chen
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | | | - Seth M Arum
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | - John Vest
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Michael Polydefkis
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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16
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Jacobs CM, Kunz M, Mahfoud F, Wagmann L, Meyer MR. 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. Anal Bioanal Chem 2023; 415:167-177. [PMID: 36318313 PMCID: PMC9816235 DOI: 10.1007/s00216-022-04394-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/06/2022] [Accepted: 10/19/2022] [Indexed: 01/07/2023]
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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Affiliation(s)
- Cathy M Jacobs
- Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany
| | - Michael Kunz
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Saarland University, Homburg, Germany
| | - Felix Mahfoud
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Saarland University, Homburg, Germany
- Institute for Medical Engineering and Science, MIT, Cambridge, MA, USA
| | - Lea Wagmann
- Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany
| | - Markus R Meyer
- Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany.
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17
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Leonova MV. On the issue of low adherence of patients to antihypertensive therapy: the use of therapeutic drug monitoring of drugs: A review. CONSILIUM MEDICUM 2022. [DOI: 10.26442/20751753.2022.10.201872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Low adherence of patients to antihypertensive therapy remains an urgent problem and is recognized as the main cause of insufficient BP control at the population level. In this regard, to increase the motivation of patients in clinical practice, methods for assessing adherence (compliance) to drugs. Along with indirect assessment methods (questionnaires, self-reports, pill counts, etc.), which, however, do not always reflect the real patients adherence, more objective is the measurement of antihypertensive drug concentrations in physiological fluids therapeutic drug monitoring (TDM). For these purposes, methods of high-performance liquid chromatography with mass spectrometry were recently adapted, reference ranges of antihypertensive drug concentrations in blood serum and urine for standard doses of drugs were determined, as well as criteria for assessing complete or partial non-compliance. There have been a number of studies using TDM to assess adherence, which show a high rate of non-compliance (low compliance) of more than 50% of cases with a variability from 25 to 86.1%, with complete non-compliance 10.134.5% in patients with uncontrolled and/or resistant hypertension (3 antihypertensive drug). In a population of patients with a normal course of hypertension, taking 12 antihypertensive drug, the level of non-compliance according to the results of TDM did not exceed 10%. Comparison of the TDM method with indirect methods of assessing adherence did not reveal consistency; at the same time, the detection of antihypertensive drug better characterized the clinical problems of patients with arterial hypertension. In clinical practice, direct assessment methods (TDM) can be used to measure adherence in problem patients with uncontrolled hypertension and high cardiovascular risk despite optimal therapy.
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18
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Nikrýnová Nguyen TMP, Štrauch B, Petrák O, Krátká Z, Holaj R, Kurcová I, Marešová V, Pilková A, Hartinger J, Waldauf P, Zelinka T, Widimský J. Adherence and blood pressure control in patients with primary aldosteronism. Blood Press 2022; 31:58-63. [PMID: 35438025 DOI: 10.1080/08037051.2022.2061416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
PURPOSE The aim of our study was to evaluate the adherence to mineralocorticoid receptor (MR) antagonists and other antihypertensive therapy and blood pressure control in conservatively treated patients with primary aldosteronism (PA). MATERIALS AND METHODS Conservatively treated subjects with previously confirmed PA (n-50, 64.5 ± 9 years of age, 24% women) were investigated via our outpatient hypertension clinic. All subjects underwent regular examinations in our clinic. In addition to basic laboratory and clinical parameters, 24 h ambulatory blood pressure monitoring (ABPM) (Spacelabs) was evaluated. Unplanned blood sampling for assessment of serum antihypertensive drug concentrations by the means of liquid chromatography-mass spectrometry was performed in all patients. In case of spironolactone, its active metabolite canrenone was also evaluated. Total non-compliance was then defined as the absence of all measured antihypertensive drugs. Partial non-compliance was calculated as the absence of serum levels of at least one, but not all antihypertensive drugs prescribed. RESULTS Good blood pressure control was detected (mean 24 h systolic/diastolic BP 130 ± 12/77 ± 9 mmHg). The average number of antihypertensive drugs was 3.9 ± 1.5. All subjects were treated by MR antagonists. 44% of patients received spironolactone (average daily dose 45 ± 20 mg) and in the remaining 56% of subjects eplerenone was administered (average daily dose 80 ± 30 mg) due to spironolactone side effects. Assessment of antihypertensive drug concentrations revealed full adherence in 80% of all subjects, partial nonadherence was noted in the remaining 20% of subjects. MR antagonist levels were detected in almost all subjects (49 out of 50). CONCLUSIONS Good blood pressure control and adherence to therapy were detected in conservatively treated patients with PA. Eplerenone had to be used quite often as male subjects did not tolerate dose escalation due to spironolactone side effects.
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Affiliation(s)
- Thi Minh Phuong Nikrýnová Nguyen
- Third Internal Department of Endocrinology and Metabolism, General University Hospital, Charles University, Prague, Czech Republic
| | | | - Ondřej Petrák
- Third Internal Department of Endocrinology and Metabolism, General University Hospital, Charles University, Prague, Czech Republic
| | - Zuzana Krátká
- Third Internal Department of Endocrinology and Metabolism, General University Hospital, Charles University, Prague, Czech Republic
| | - Robert Holaj
- Third Internal Department of Endocrinology and Metabolism, General University Hospital, Charles University, Prague, Czech Republic
| | - Ivana Kurcová
- Institute of Forensic Medicine and Toxicology, Toxicology Laboratory, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Věra Marešová
- Institute of Forensic Medicine and Toxicology, Toxicology Laboratory, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alena Pilková
- Department of Clinical Pharmacology and Pharmacy, First Faculty of Medicine, Institute of Pharmacology, Charles University and General University Hospital, Prague, Czech Republic
| | - Jan Hartinger
- Department of Clinical Pharmacology and Pharmacy, First Faculty of Medicine, Institute of Pharmacology, Charles University and General University Hospital, Prague, Czech Republic
| | - Petr Waldauf
- Department of Anesthesiology and Intensive Care Medicine, Third Faculty of Medicine and FNKV University Hospital, Charles University, Prague, Czech Republic
| | - Tomáš Zelinka
- Third Internal Department of Endocrinology and Metabolism, General University Hospital, Charles University, Prague, Czech Republic
| | - Jiří Widimský
- Third Internal Department of Endocrinology and Metabolism, General University Hospital, Charles University, Prague, Czech Republic
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19
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Avataneo V, Fanelli E, De Nicolò A, Rabbia F, Palermiti A, Pappaccogli M, Cusato J, De Rosa FG, D'Avolio A, Veglio F. A Non-Invasive Method for Detection of Antihypertensive Drugs in Biological Fluids: The Salivary Therapeutic Drug Monitoring. Front Pharmacol 2022; 12:755184. [PMID: 35069191 PMCID: PMC8766966 DOI: 10.3389/fphar.2021.755184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 10/29/2021] [Indexed: 11/25/2022] Open
Abstract
Objectives: Arterial hypertension is still the most frequent cause of cardiovascular and cerebrovascular morbidity and mortality. Antihypertensive treatment has proved effective in reduction of cardiovascular risk. Nevertheless, lifestyle interventions and pharmacological therapy in some cases are ineffective in reaching blood pressure target values, despite full dose and poly-pharmacological treatment. Poor adherence to medications is an important cause of treatment failure. Different methods to assess therapeutic adherence are currently available: Therapeutic drug monitoring in biological fluids has previously demonstrated its efficacy and reliability. Plasma and urine have been already used for this purpose, but they may be affected by some practical limitations. Saliva may represent a feasible alternative. Methods: Fourteen antihypertensive drugs and two metabolites were simultaneously tested in plasma, urine, and saliva. Tested molecules included: atenolol, nebivolol, clonidine, ramipril, olmesartan, telmisartan, valsartan, amlodipine, nifedipine, doxazosin, chlorthalidone, hydrochlorothiazide, indapamide, sacubitril, ramiprilat, and sacubitrilat. Therapeutic drug monitoring was performed using ultra-high performance liquid chromatography, coupled to tandem mass spectrometry (UHPLC-MS/MS). The method has been preliminarily evaluated in a cohort of hypertensive patients. Results: The method has been validated according to US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The application on a cohort of 32 hypertensive patients has demonstrated sensibility and specificity of 98% and 98.1%, respectively, with a good feasibility in real-life clinical practice. Conclusion: Saliva may represent a feasible biological sample for therapeutic drug monitoring by non-invasive collection, prompt availability, and potential accessibility also in out-of-clinic settings.
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Affiliation(s)
- Valeria Avataneo
- Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Elvira Fanelli
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, A.O.U. Città Della Salute e Della Scienza di Torino, University of Turin, Turin, Italy
| | - Amedeo De Nicolò
- Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Franco Rabbia
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, A.O.U. Città Della Salute e Della Scienza di Torino, University of Turin, Turin, Italy
| | - Alice Palermiti
- Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Marco Pappaccogli
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, A.O.U. Città Della Salute e Della Scienza di Torino, University of Turin, Turin, Italy
| | - Jessica Cusato
- Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Francesco Giuseppe De Rosa
- Division of Infectious Diseases, Department of Medical Sciences, A.O.U. Città Della Salute e Della Scienza di Torino, University of Turin, Turin, Italy
| | - Antonio D'Avolio
- Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Franco Veglio
- Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, A.O.U. Città Della Salute e Della Scienza di Torino, University of Turin, Turin, Italy
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20
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Lane D, Lawson A, Burns A, Azizi M, Burnier M, Jones DJL, Kably B, Khunti K, Kreutz R, Patel P, Persu A, Spiering W, Toennes SW, Tomaszewski M, Williams B, Gupta P, Dasgupta I. Nonadherence in Hypertension: How to Develop and Implement Chemical Adherence Testing. Hypertension 2022; 79:12-23. [PMID: 34739765 DOI: 10.1161/hypertensionaha.121.17596] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Nonadherence to antihypertensive medication is common, especially in those with apparent treatment-resistant hypertension (true treatment-resistant hypertension requires exclusion of nonadherence), and its routine detection is supported by clinical guidelines. Chemical adherence testing is a reliable and valid method to detect adherence, yet methods are unstandardized and are not ubiquitous. This article describes the principles of chemical adherence testing for hypertensive patients and provides a set of recommendations for centers wishing to develop the test. We recommend testing should be done in either of two instances: (1) in those who have resistant hypertension or (2) in those on 2 antihypertensives who have a less than 10 mm Hg drop in systolic blood pressure on addition of the second antihypertensive medication. Furthermore, we recommend that verbal consent is secured before undertaking the test, and the results should be discussed with the patient. Based on medications prescribed in United Kingdom, European Union, and United States, we list top 20 to 24 drugs that cover >95% of hypertension prescriptions which may be included in the testing panel. Information required to identify these medications on mass spectrometry platforms is likewise provided. We discuss issues related to ethics, sample collection, transport, stability, urine versus blood samples, qualitative versus quantitative testing, pharmacokinetics, instrumentation, validation, quality assurance, and gaps in knowledge. We consider how to best present, interpret, and discuss chemical adherence test results with the patient. In summary, this guidance should help clinicians and their laboratories in the development of chemical adherence testing of prescribed antihypertensive drugs.
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Affiliation(s)
- Dan Lane
- The Department of Chemical Pathology and Metabolic Diseases, Level 4, Sandringham Building, Leicester Royal Infirmary, United Kingdom (D.L., P.P., P.G.)
- Leicester Diabetes Centre, University of Leicester, Leicester General Hospital, Leicester, United Kingdom (D.L., K.K.)
| | - Alexander Lawson
- Department of Clinical Chemistry, Immunology and Toxicology, Heartlands Hospital University Hospitals Birmingham, United Kingdom (A.L.)
| | - Angela Burns
- Department of Clinical Biochemistry, Queen Elizabeth University Hospital, Glasgow, United Kingdom (A.B.)
| | - Michel Azizi
- Université de Paris, Inserm CIC1418, Paris, France (M.A.)
- APHP, Hypertension Unit, Hôpital Européen Georges Pompidou, Paris, France (M.A.)
| | - Michel Burnier
- Service of Nephrology and Hypertension, University Hospital, Lausanne, Switzerland (M.B.)
| | - Donald J L Jones
- Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom (D.J.L.J., P.P., P.G.)
| | - Benjamin Kably
- Université de Paris, France (B.K.)
- APHP, Pharmacology Unit, Hôpital Européen Georges Pompidou, Paris, France (B.K.)
| | - Kamlesh Khunti
- Leicester Diabetes Centre, University of Leicester, Leicester General Hospital, Leicester, United Kingdom (D.L., K.K.)
| | - Reinhold Kreutz
- Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, Germany (R.K.)
| | - Prashanth Patel
- The Department of Chemical Pathology and Metabolic Diseases, Level 4, Sandringham Building, Leicester Royal Infirmary, United Kingdom (D.L., P.P., P.G.)
- Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom (D.J.L.J., P.P., P.G.)
| | - Alexandre Persu
- Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium/Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain (A.P.)
| | - Wilko Spiering
- Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, the Netherlands (W.S.)
| | - Stefan W Toennes
- Institute of Legal Medicine, Department of Forensic Toxicology, University Hospital, Goethe University, Frankfurt, Germany (S.W.T.)
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom (M.T.)
- Manchester Heart Centre, Manchester University National Health Service Foundation Trust, United Kingdom (M.T.)
| | - Bryan Williams
- Department of Cardiovascular Sciences, University College London, United Kingdom (B.W.)
| | - Pankaj Gupta
- The Department of Chemical Pathology and Metabolic Diseases, Level 4, Sandringham Building, Leicester Royal Infirmary, United Kingdom (D.L., P.P., P.G.)
- Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom (D.J.L.J., P.P., P.G.)
| | - Indranil Dasgupta
- Renal Unit, Heartlands Hospital, Birmingham and Warwick Medical School, University of Warwick, Coventry, United Kingdom (I.D.)
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21
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Kulkarni S, Rao R, Goodman JDH, Connolly K, O'Shaughnessy KM. Nonadherence to antihypertensive medications amongst patients with uncontrolled hypertension: A retrospective study. Medicine (Baltimore) 2021; 100:e24654. [PMID: 33832064 PMCID: PMC8036043 DOI: 10.1097/md.0000000000024654] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/24/2020] [Accepted: 01/09/2021] [Indexed: 01/05/2023] Open
Abstract
ABSTRACT Medication nonadherence represents a modifiable risk factor for patients with hypertension. Identification of nonadherent patients could have significant clinical and economic implications in the management of uncontrolled hypertension.We analysed the results of 174 urinary adherence screens from patients referred to Addenbrooke's Hospital, Cambridge, for uncontrolled hypertension. Cases were identified for evaluation by results of liquid chromatography-tandem mass spectrometry of urine samples (males: 91; females: 83; age range: 17-87). We performed a binary logistic regression analysis for nonadherence using age, sex, and number of medications prescribed (both antihypertensives and non-antihypertensives separately) as independent predictors. Rates of nonadherence for individual antihypertensive drugs were calculated if prescribed to ≥10 patients.The overall rate of nonadherence to one or more prescribed antihypertensive medications was 40.3%. 14.4% of all patients were nonadherent to all prescribed antihypertensive medications (complete nonadherence), whereas 25.9% of all patients were nonadherent to at least 1, (but not all) prescribed antihypertensive medications (partial nonadherence). 72% of patients were prescribed ≥3 antihypertensives And for every increase in the number of antihypertensive medications prescribed, nonadherence increased with adjusted odds ratios of 2.9 (P < .001). Logistic regression showed that women were 3.3 times more likely to be nonadherent (P = .004). Polypharmacy (≥6 medications prescribed for hypertension and/or concomitant comorbidities) was prevalent in 52%. Bendroflumethiazide and chlortalidone demonstrated the highest and lowest nonadherences respectively (45.5% and 11.8%).Rate of nonadherence in patients with hypertension was significantly impacted by sex and number of antihypertensive medications prescribed. Understanding these factors is crucial in identifying and managing nonadherence.
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22
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Abstract
: Suboptimal adherence to antihypertensive medication is a major contributor to poor blood pressure control. Several methods, direct or indirect, are available for measuring adherence, including the recently developed biochemical screening, although there is no gold-standard method routinely used in clinical practice to accurately assess the different facets of adherence. Adherence to treatment is a complex phenomenon and several of the barriers to adherence will need to be addressed at the healthcare system level; however, when looking at adherence from a more practical side and from the practitioner's perspective, the patient-practitioner relationship is a key element both in detecting adherence and in attempting to choose interventions tailored to the patient's profile. The use of single-pill combinations enabling simplification of treatment regimen, the implementation of a collaborative team-based approach and the development of electronic health tools also hold promise for improving adherence, and thus impacting cardiovascular outcomes and healthcare costs.
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23
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Affiliation(s)
- Rajiv Agarwal
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, IN
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25
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Şahinarslan A, Gazi E, Aktoz M, Özkan Ç, Okyay GU, Elalmış ÖU, Belen E, Bitigen A, Derici Ü, Tütüncü NB, Yıldırır A. Consensus paper on the evaluation and treatment of resistant hypertension by the Turkish Society of Cardiology. Anatol J Cardiol 2020; 24:137-152. [PMID: 32870176 PMCID: PMC7585974 DOI: 10.14744/anatoljcardiol.2020.74154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2020] [Indexed: 02/07/2023] Open
Affiliation(s)
- Asife Şahinarslan
- Department of Cardiology, Faculty of Medicine, Gazi University; Ankara-Turkey
| | - Emine Gazi
- Department of Cardiology, Faculty of Medicine, 18 Mart University; Çanakkale-Turkey
| | - Meryem Aktoz
- Department of Cardiology, Faculty of Medicine, Trakya University; Edirne-Turkey
| | - Çiğdem Özkan
- Department of Endocrinology, İzmir Bozyaka Training and Research Hospital; İzmir-Turkey
| | - Gülay Ulusal Okyay
- Department of Nephrology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital; Ankara-Turkey
| | | | - Erdal Belen
- Department of Cardiology, İstanbul Okmeydanı State Hospital; İstanbul-Turkey
| | - Atila Bitigen
- Department of Cardiology, Fatih Medical Park Hospital; İstanbul-Turkey
| | - Ülver Derici
- Department of Nephrology, Faculty of Medicine, Gazi University; Ankara-Turkey
| | | | - Aylin Yıldırır
- Department of Cardiology, Faculty of Medicine, Başkent University; Ankara-Turkey
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Siddiqui M, Bhatt H, Judd EK, Oparil S, Calhoun DA. Reserpine Substantially Lowers Blood Pressure in Patients With Refractory Hypertension: A Proof-of-Concept Study. Am J Hypertens 2020; 33:741-747. [PMID: 32179903 DOI: 10.1093/ajh/hpaa042] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/11/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office blood pressure (AOBP) ≥130/80 mm Hg and awake ambulatory blood pressure (ABP) ≥130/80 mm Hg on ≥5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist. Previous studies suggest that RfHTN is attributable to heightened sympathetic tone. The current study tested whether reserpine, a potent sympatholytic agent, lowers blood pressure (BP) in patients with RfHTN. METHODS Twenty-one out of 45 consecutive patients with suspected RfHTN were determined to be fully adherent with their antihypertensive regimen. Seven patients agreed to participate in the current clinical trial with reserpine and 6 patients completed the study. Other sympatholytic medications, such as clonidine or guanfacine, were tapered and discontinued before starting reserpine. Reserpine 0.1 mg daily was administered in an open-label fashion for 4 weeks. All patients were evaluated by AOBP and 24-hour ABP at baseline and after 4 weeks of treatment. RESULTS Reserpine lowered mean systolic and diastolic AOBP by 29.3 ± 22.2 and 22.0 ± 15.8 mm Hg, respectively. Mean 24-hour systolic and diastolic ABPs were reduced by 21.8 ± 13.4 and 15.3 ± 9.6 mm Hg, mean awake systolic and diastolic ABPs by 23.8 ± 11.8 and 17.8 ± 9.2 mm Hg, and mean asleep systolic and diastolic ABPs by 21.5 ± 11.4 and 13.7 ± 6.4 mm Hg, respectively. CONCLUSIONS Reserpine, a potent sympatholytic agent, lowers BP in patients whose BP remained uncontrolled on maximal antihypertensive therapy, lending support to the hypothesis that excess sympathetic output contributes importantly to the development of RfHTN.
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Affiliation(s)
- Mohammed Siddiqui
- Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Hemal Bhatt
- Division of Cardiology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Eric K Judd
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Suzanne Oparil
- Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - David A Calhoun
- Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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27
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Nonadherence to antihypertensive medications is related to pill burden in apparent treatment-resistant hypertensive individuals. J Hypertens 2020; 38:1165-1173. [DOI: 10.1097/hjh.0000000000002398] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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28
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Tanna S, Ogwu J, Lawson G. Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives. ACTA ACUST UNITED AC 2020; 58:643-663. [DOI: 10.1515/cclm-2019-0820] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 11/19/2019] [Indexed: 11/15/2022]
Abstract
AbstractNonadherence to prescribed pharmacotherapy is an understated public health problem globally and is costing many patients their chance to return to good health and healthcare systems billions. Clinicians need an accurate assessment of adherence to medications to aid the clinical decision-making process in the event of poor patient progress and to maximise the patient health outcomes from the drug therapies prescribed. An overview of indirect and direct methods used to measure medication adherence is presented, highlighting the potential for accurate measuring of drugs in biological samples using hyphenated mass spectrometry (MS) techniques to provide healthcare professionals with a reliable evidence base for clinical decision making. In this review we summarise published applications of hyphenated MS techniques for a diverse range of clinical areas demonstrating the rise in the use of such direct methods for assessing medication adherence. Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods using plasma, serum and urine samples are the most popular, in recent years increased attention has been given to liquid chromatography high-resolution mass spectrometry (LC-HRMS) methods and alternative biosample matrices including hair, saliva and blood microsamples. The advantages and challenges of using hyphenated MS techniques to address this healthcare problem are also discussed alongside future perspectives.
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Affiliation(s)
- Sangeeta Tanna
- Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester, UK
| | - John Ogwu
- Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester, UK
| | - Graham Lawson
- Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester, UK
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29
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Jaffe G, Gray Z, Krishnan G, Stedman M, Zheng Y, Han J, Chertow GM, Leppert JT, Bhalla V. Screening Rates for Primary Aldosteronism in Resistant Hypertension: A Cohort Study. Hypertension 2020; 75:650-659. [PMID: 32008436 DOI: 10.1161/hypertensionaha.119.14359] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Resistant hypertension is associated with higher rates of cardiovascular disease, kidney disease, and death than primary hypertension. Although clinical practice guidelines recommend screening for primary aldosteronism among persons with resistant hypertension, rates of screening are unknown. We identified 145 670 persons with hypertension and excluded persons with congestive heart failure or advanced chronic kidney disease. Among this cohort, we studied 4660 persons ages 18 to <90 from the years 2008 to 2014 with resistant hypertension and available laboratory tests within the following 24 months. The screening rate for primary aldosteronism in persons with resistant hypertension was 2.1%. Screened persons were younger (55.9±13.3 versus 65.5±11.6 years; P<0.0001) and had higher systolic (145.1±24.3 versus 139.6±20.5 mm Hg; P=0.04) and diastolic blood pressure (81.8±13.6 versus 74.4±13.8 mm Hg; P<0.0001), lower rates of coronary artery disease (5.2% versus 14.2%; P=0.01), and lower serum potassium concentrations (3.9±0.6 versus 4.1±0.5 mmol/L; P=0.04) than unscreened persons. Screened persons had significantly higher rates of prescription for calcium channel blockers, mixed α/β-adrenergic receptor antagonists, sympatholytics, and vasodilators, and lower rates of prescription for loop, thiazide, and thiazide-type diuretics. The prescription of mineralocorticoid receptor antagonists or other potassium-sparing diuretics was not significantly different between groups (P=0.20). In conclusion, only 2.1% of eligible persons received a screening test within 2 years of meeting criteria for resistant hypertension. Low rates of screening were not due to the prescription of antihypertensive medications that may potentially interfere with interpretation of the screening test. Efforts to highlight guideline-recommended screening and targeted therapy are warranted.
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Affiliation(s)
- Gilad Jaffe
- From the Stanford Hypertension Center (G.J., Z.G., M.S., G.M.C., V.B.), Stanford University School of Medicine, CA
| | - Zachary Gray
- From the Stanford Hypertension Center (G.J., Z.G., M.S., G.M.C., V.B.), Stanford University School of Medicine, CA
| | - Gomathi Krishnan
- Research Informatics Center (G.K.), Stanford University School of Medicine, CA
| | - Margaret Stedman
- From the Stanford Hypertension Center (G.J., Z.G., M.S., G.M.C., V.B.), Stanford University School of Medicine, CA.,Division of Nephrology, Department of Medicine (M.S., Y.Z., J.H., G.M.C., J.T.L., V.B.), Stanford University School of Medicine, CA
| | - Yuanchao Zheng
- Division of Nephrology, Department of Medicine (M.S., Y.Z., J.H., G.M.C., J.T.L., V.B.), Stanford University School of Medicine, CA
| | - Jialin Han
- Division of Nephrology, Department of Medicine (M.S., Y.Z., J.H., G.M.C., J.T.L., V.B.), Stanford University School of Medicine, CA
| | - Glenn M Chertow
- From the Stanford Hypertension Center (G.J., Z.G., M.S., G.M.C., V.B.), Stanford University School of Medicine, CA.,Division of Nephrology, Department of Medicine (M.S., Y.Z., J.H., G.M.C., J.T.L., V.B.), Stanford University School of Medicine, CA
| | - John T Leppert
- Division of Nephrology, Department of Medicine (M.S., Y.Z., J.H., G.M.C., J.T.L., V.B.), Stanford University School of Medicine, CA.,Department of Urology (J.T.L.), Stanford University School of Medicine, CA
| | - Vivek Bhalla
- From the Stanford Hypertension Center (G.J., Z.G., M.S., G.M.C., V.B.), Stanford University School of Medicine, CA.,Division of Nephrology, Department of Medicine (M.S., Y.Z., J.H., G.M.C., J.T.L., V.B.), Stanford University School of Medicine, CA
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30
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Abstract
The global epidemic of hypertension is largely uncontrolled and hypertension remains the leading cause of noncommunicable disease deaths worldwide. Suboptimal adherence, which includes failure to initiate pharmacotherapy, to take medications as often as prescribed, and to persist on therapy long-term, is a well-recognized factor contributing to the poor control of blood pressure in hypertension. Several categories of factors including demographic, socioeconomic, concomitant medical-behavioral conditions, therapy-related, healthcare team and system-related factors, and patient factors are associated with nonadherence. Understanding the categories of factors contributing to nonadherence is useful in managing nonadherence. In patients at high risk for major adverse cardiovascular outcomes, electronic and biochemical monitoring are useful for detecting nonadherence and for improving adherence. Increasing the availability and affordability of these more precise measures of adherence represent a future opportunity to realize more of the proven benefits of evidence-based medications. In the absence of new antihypertensive drugs, it is important that healthcare providers focus their attention on how to do better with the drugs they have. This is the reason why recent guidelines have emphasize the important need to address drug adherence as a major issue in hypertension management.
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Affiliation(s)
- Michel Burnier
- From the Service of Nephrology and Hypertension, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (M.B.)
| | - Brent M Egan
- Department of Medicine, Care Coordination Institute, University of South Carolina School of Medicine, Greenville, SC (B.M.E.)
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31
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Siddiqui M, Judd EK, Dudenbostel T, Gupta P, Tomaszewski M, Patel P, Oparil S, Calhoun DA. Antihypertensive Medication Adherence and Confirmation of True Refractory Hypertension. Hypertension 2019; 75:510-515. [PMID: 31813346 DOI: 10.1161/hypertensionaha.119.14137] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Refractory hypertension (RfHTN) is a phenotype of antihypertensive treatment failure defined as uncontrolled BP despite the use of effective doses of ≥5 antihypertensive medications including a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist. The degree of medication nonadherence is unknown among patients with RfHTN. In this prospective evaluation, 54 patients with apparent RfHTN were recruited from the University of Alabama at Birmingham Hypertension Clinic after having uncontrolled BP at 3 or more clinic visits. All patients' BP was evaluated by automated office BP and 24-hour ambulatory BP monitoring (n=49). Antihypertensive medication adherence was determined by measuring 24-hour urine specimens for antihypertensive medications and their metabolites by high-performance liquid chromatography-tandem mass spectrometry (n=45). Of the 45 patients who completed 24-hour ambulatory BP monitoring, 40 (88.9%) had confirmed RfHTN based on an elevated automated office BP (≥130/80 mm Hg), mean 24-hour ABP (≥125/75 mm Hg), and mean awake (day-time) ABP (≥130/80 mm Hg). Out of the 40 fully evaluated patients with RfHTN, 16 (40.0%) were fully adherent with all prescribed medications. Eighteen (45.0%) patients were partially adherent and 6 (15.0%) had none of the prescribed agents detected in their urine. Of 18 patients who were partially adherent, 5 (12.5%) were adherent with at least 5 medications, including chlorthalidone and the mineralocorticoid receptor antagonist, consistent with true RfHTN. Of patients identified as having apparent RfHTN, 52.5% were adherent with at least 5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist, confirming true RfTHN. These findings validate RfHTN as a rare, but true phenotype of antihypertensive treatment failure.
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Affiliation(s)
- Mohammed Siddiqui
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
| | - Eric K Judd
- Division of Nephrology (E.K.J.), University of Alabama at Birmingham
| | - Tanja Dudenbostel
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
| | - Pankaj Gupta
- Department of Metabolic Diseases and Chemical Pathology, University Hospitals of Leicester NHS Trust, United Kingdom (P.G., P.P.).,Department of Cardiovascular Sciences, University of Leicester, United Kingdom (P.G., P.P.)
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom (M.T.)
| | - Prashanth Patel
- Department of Metabolic Diseases and Chemical Pathology, University Hospitals of Leicester NHS Trust, United Kingdom (P.G., P.P.).,Department of Cardiovascular Sciences, University of Leicester, United Kingdom (P.G., P.P.)
| | - Suzanne Oparil
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
| | - David A Calhoun
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
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32
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Hamdidouche I, Gosse P, Cremer A, Lorthioir A, Delsart P, Courand PY, Denolle T, Halimi JM, Girerd X, Ormezzano O, Rossignol P, Pereira H, Azizi M, Amar L, Bobrie G, Monge M, Pagny JY, Sapoval M, Claisse G, Midulla M, Mounier-Vehier C, Dauphin R, Fauvel JP, Lantelme P, Rouvière O, Grenier N, Lebras Y, Trillaud H, Dourmap C, Heautot JF, Larralde A, Paillard F, Cluzel P, Rosenbaum D, Alison D, Popovic B, Zannad F, Baguet JP, Thony F, Bartoli JM, Vaïsse B, Drouineau J, Herpin D, Sosner P, Tasu JP, Velasco S, Ribstein J, Kovacsik H, Bouhanick B, Chamontin B, Rousseau H, Le Jeune S, Lopez-Sublet M, Mourad JJ, Bellmann L, Esnault V, Ferrari E, Chatellier G. Clinic Versus Ambulatory Blood Pressure in Resistant Hypertension: Impact of Antihypertensive Medication Nonadherence. Hypertension 2019; 74:1096-1103. [DOI: 10.1161/hypertensionaha.119.13520] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Clinic-ambulatory blood pressure (BP) difference is influenced by patients- and device-related factors and inadequate clinic-BP measurement. We investigated whether nonadherence to antihypertensive medications may also influence this difference in a post hoc analysis of the DENERHTN trial (Renal Denervation for Hypertension). We pooled the data of 77 out of 106 evaluable patients with apparent resistant hypertension who received a standardized antihypertensive treatment and had both ambulatory BP and drug-screening results available at baseline after 1 month of standardized triple therapy and at 6 months on a median of 5 antihypertensive drugs. After drug assay samplings on study visits, patients took their antihypertensive treatment under supervision immediately after the start of the ambulatory BP recording, and supine clinic BP was measured 24 hours post-dosing; both allowed to calculate the clinic minus daytime ambulatory systolic BP (SBP) difference (clinic-SBP–day-SBP). A total of 29 (37.7%) were found nonadherent to medications at baseline and 38 (49.4%) at 6 months. At baseline, the mean clinic-SBP–day-SBP difference in the nonadherent group was 12.7 mm Hg (95% CI, 7.8–17.7 mm Hg,
P
<0.001). In contrast, clinic SBP was almost identical to day-SBP in the adherent group (clinic-SBP–day-SBP difference, 0.1 mm Hg; 95% CI, −3.3 to 3.5 mm Hg;
P
=0.947). Similar observations were made at 6 months. Using receiver operating characteristics curves, we found that a 6 mm Hg cutoff of clinic-SBP–day-SBP difference had 67% sensitivity and 69% specificity to predict nonadherence to the triple therapy at baseline. In conclusion, a large clinic-SBP–day-SBP difference may help discriminating between adherence and nonadherence to treatment in patients with resistant hypertension.
Clinical Trial Registration—
URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01570777.
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Affiliation(s)
- Idir Hamdidouche
- From the INSERM, Centre d’Investigations Cliniques- Plurithématique 1418, Paris, France (I.H., H.P., M.A.)
| | - Philippe Gosse
- ESH Hypertension excellence center, Hopital Saint André, University hospital of Bordeaux, France (P.G., A.C.)
| | | | - Aurelien Lorthioir
- AP-HP, Hypertension unit and DMU CARTE, Hôpital Européen Georges-Pompidou, Paris, France (A.L., H.P., M.A.)
| | - Pascal Delsart
- CHU Lille, Institut Cœur Poumon, Bd Pr Leclercq, France (P.D.)
| | - Pierre-Yves Courand
- Cardiology department, European Society of Hypertension Excellence Center, Hôpital de la Croix-Rousse et Hôpital Lyon Sud, Hospices Civils de Lyon, France (P.-Y.C.)
- Université de Lyon, CREATIS; CNRS UMR5220; INSERM U1044; INSA-Lyon; Université Claude Bernard Lyon 1, France (P.-Y.C.)
| | - Thierry Denolle
- Hĉpital Arthur Gardiner, Centre d’Excellence en HTA Rennes- Dinard, France (T.D.)
| | - Jean-Michel Halimi
- Service de nephrologie-immunologie clinique, Hopital universitaire de Tours, et EA4245 Université Francois Rabelais, France (J.-M.H.)
| | - Xavier Girerd
- Unité de Prévention Cardio Vasculaire, Groupe Hospitalier Universitaire Pitié-Salpêtrière–Institut IE3M, Paris, France (X.G)
| | - Olivier Ormezzano
- Department of Cardiology, University Hospital and INSERM U1039, Bioclinic Radiopharmaceutics Laboratory, Grenoble, France (O.O.)
| | - Patrick Rossignol
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques- Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (P.R.)
| | - Helena Pereira
- From the INSERM, Centre d’Investigations Cliniques- Plurithématique 1418, Paris, France (I.H., H.P., M.A.)
- AP-HP, Hypertension unit and DMU CARTE, Hôpital Européen Georges-Pompidou, Paris, France (A.L., H.P., M.A.)
- AP-HP Clinical and Epidemiological Unit, Hopital Europeen Georges Pompidou, Paris, France (H.P.)
| | - Michel Azizi
- From the INSERM, Centre d’Investigations Cliniques- Plurithématique 1418, Paris, France (I.H., H.P., M.A.)
- AP-HP, Hypertension unit and DMU CARTE, Hôpital Européen Georges-Pompidou, Paris, France (A.L., H.P., M.A.)
- Université de Paris, Paris, France (M.A.)
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Lamirault G, Artifoni M, Daniel M, Barber-Chamoux N, Nantes University Hospital Working Group On Hypertension. Resistant Hypertension: Novel Insights. Curr Hypertens Rev 2019; 16:61-72. [PMID: 31622203 DOI: 10.2174/1573402115666191011111402] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/05/2019] [Accepted: 09/12/2019] [Indexed: 12/27/2022]
Abstract
Hypertension is the most common chronic disease and the leading risk factor for disability and premature deaths in the world, accounting for more than 9 million deaths annually. Resistant hypertension is a particularly severe form of hypertension. It was described 50 years ago and since then has been a very active field of research. This review aims at summarizing the most recent findings on resistant hypertension. The recent concepts of apparent- and true-resistant hypertension have stimulated a more precise definition of resistant hypertension taking into account not only the accuracy of blood pressure measurement and pharmacological class of prescribed drugs but also patient adherence to drugs and life-style recommendations. Recent epidemiological studies have reported a 10% prevalence of resistant hypertension among hypertensive subjects and demonstrated the high cardiovascular risk of these patients. In addition, these studies identified subgroups of patients with even higher morbidity and mortality risk, probably requiring a more aggressive medical management. In the meantime, guidelines provided more standardized clinical work-up to identify potentially reversible causes for resistant hypertension such as secondary hypertension. The debate is however still ongoing on which would be the optimal method(s) to screen for non-adherence to hypertension therapy, recognized as the major cause for (pseudo)-resistance to treatment. Recent randomized clinical trials have demonstrated the strong benefit of anti-aldosterone drugs (mostly spironolocatone) as fourth-line therapies in resistant hypertension whereas clinical trials with device-based therapies displayed contrasting results. New trials with improved devices and more carefully selected patients with resistant hypertension are ongoing.
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Affiliation(s)
- Guillaume Lamirault
- l'institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.,l'institut du Thorax, CHU Nantes, Service de Cardiologie, Nantes, France
| | | | - Mélanie Daniel
- Clinical Pharmacology Centre (INSERM CIC1505), CHU Clermont-Ferrand, France
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Kichou B, Henine N, Himeur Y, Kichou L, Ait Said M, Mazeghrane A, Hammouche A. [Assessment of adherence to antihypertensive drugs in patients with resistant hypertension receiving optimal treatment]. Ann Cardiol Angeiol (Paris) 2019; 68:264-268. [PMID: 31471039 DOI: 10.1016/j.ancard.2019.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 07/19/2019] [Indexed: 11/24/2022]
Abstract
OBJECTIVES The primary objective was to estimate the proportion of non-adherence to antihypertensive drugs in patients with an apparently resistant hypertension despite optimal medical treatment. The secondary objective was to identify related factors to poor adherence. METHODS Monocentric, prospective and observational study, including consecutive patients, managed for an apparently resistant hypertension between January 2014 and December 2017, with an ambulatory blood pressure measurement (ABP) in the past year and a thorough etiological work up in the 2 past years. Hypertension was considered resistant if the daytime ABP was ≥ 135/85mmHg and/or the 24hours ABP≥to 130/80mmHg, despite 4 antihypertensive medications at optimal doses. Adherence to treatment was assessed by the eight-item Morisky Scale (MMAS-8). RESULTS We enrolled 386 patients, with a mean age of 64.6 years, and 48.2% of men. The mean office blood pressure, 24hours and daytime APB were 178.6/101.3mmHg, 164.4/97.2mmHg and 170.5/99.7mmHg respectively. The proportions of low, medium and high adherence were 24.5%, 47.6% and 27.9% respectively. Associated-factors with poor adherence were female sex, low education level, celibacy, polypharmacy and lack of home self-blood pressure monitoring. CONCLUSION Over two out of three patients with an apparently resistant hypertension under optimal treatment were partially or fully nonadherent to treatment in our study. Assessment of adherence would be systematic in these patients before implementing complex investigations or non-pharmacologic invasive procedures.
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Affiliation(s)
- B Kichou
- Service de cardiologie, centre hospitalier universitaire de Tizi-Ouzou, 15000, Tizi-Ouzou, Algérie.
| | - N Henine
- Service de cardiologie, centre hospitalier universitaire de Tizi-Ouzou, 15000, Tizi-Ouzou, Algérie
| | - Y Himeur
- Service de cardiologie, centre hospitalier universitaire de Tizi-Ouzou, 15000, Tizi-Ouzou, Algérie
| | - L Kichou
- Service de cardiologie, centre hospitalier universitaire de Tizi-Ouzou, 15000, Tizi-Ouzou, Algérie
| | - M Ait Said
- Service de cardiologie, centre hospitalier universitaire de Tizi-Ouzou, 15000, Tizi-Ouzou, Algérie
| | - A Mazeghrane
- Service de cardiologie, centre hospitalier universitaire de Tizi-Ouzou, 15000, Tizi-Ouzou, Algérie
| | - A Hammouche
- Service de cardiologie, centre hospitalier universitaire de Tizi-Ouzou, 15000, Tizi-Ouzou, Algérie
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Kvasnička J, Lambert L, Waldauf P, Zelinka T, Petrák O, Štrauch B, Holaj R, Indra T, Krátká Z, Klímová J, Václavík J, Kociánová E, Nykl I, Jiravský O, Rappová G, Táborský M, Branny M, Widimský J, Rosa J. (Prediction of long-term renal denervation efficacy). COR ET VASA 2019. [DOI: 10.1016/j.crvasa.2018.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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36
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Siddiqui M, Judd EK, Dudenbostel T, Zhang B, Gupta P, Tomaszewski M, Patel P, Oparil S, Calhoun DA. Masked Uncontrolled Hypertension Is Not Attributable to Medication Nonadherence. Hypertension 2019; 74:652-659. [PMID: 31327263 DOI: 10.1161/hypertensionaha.119.13258] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (BP; <135/85 mm Hg) in-clinic but uncontrolled out-of-clinic BP by ambulatory BP monitoring (awake [daytime] readings ≥135/85 mm Hg or 24-hour readings ≥130/80 mm Hg). To determine whether MUCH is attributable to antihypertensive medication nonadherence. One hundred eighty-four enrolled patients were confirmed to have controlled office BP; of these, 167 patients were with adequate 24-hour ambulatory BP recordings. Of 167 patients, 86 were controlled by in-clinic BP assessment but had uncontrolled ambulatory awake BP, indicative of MUCH. The remaining 81 had controlled in-clinic and ambulatory awake BP, consistent with true controlled hypertension. After exclusion of 9 patients with missing 24-hour urine collections, antihypertensive medication adherence was determined based on the detection of urinary drugs or drug metabolites by high-performance liquid chromatography-tandem mass spectrometry. Of the 81 patients with MUCH, 69 (85.2%) were fully adherent and 12 (14.8%) were partially adherent (fewer medications detected than prescribed). Of the 77 patients with true controlled hypertension, 69 (89.6%) were fully adherent with prescribed antihypertensive medications and 8 (10.4%) were partially adherent. None of the patients in either group were fully nonadherent. There was no statistically significant difference in complete or partial adherence between the MUCH and true controlled groups (P=0.403). Measurement of urinary drug and drug metabolite levels demonstrates a similarly high level of antihypertensive medication adherence in both MUCH and truly controlled hypertensive patients. These findings indicate that MUCH is not attributable to antihypertensive medication nonadherence.
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Affiliation(s)
- Mohammed Siddiqui
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
| | - Eric K Judd
- Division of Nephrology (E.K.J.), University of Alabama at Birmingham
| | - Tanja Dudenbostel
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
| | - Bin Zhang
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, OH (B.Z.).,Department of Pediatrics, University of Cincinnati College of Medicine, University of Cincinnati, OH (B.Z.)
| | - Pankaj Gupta
- Department of Chemical Pathology and Metabolic Medicine, University Hospitals of Leicester NHS Trust, United Kingdom (P.G., P.P.).,Department of Cardiovascular Sciences, University of Leicester, United Kingdom (P.G., P.P.)
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom (M.T.)
| | - Prashanth Patel
- Department of Chemical Pathology and Metabolic Medicine, University Hospitals of Leicester NHS Trust, United Kingdom (P.G., P.P.).,Department of Cardiovascular Sciences, University of Leicester, United Kingdom (P.G., P.P.)
| | - Suzanne Oparil
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
| | - David A Calhoun
- From the Vascular Biology and Hypertension Program (M.S., T.D., S.O., D.A.C.), University of Alabama at Birmingham
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Hjørnholm U, Larstorp ACK, Andersen MH, Høieggen A. Directly observed therapy prior to ambulatory blood pressure measurement (DOT-HTN) in uncontrolled hypertensive patients - Effect on blood pressure, safety and patient perception. Blood Press 2019; 28:327-335. [DOI: 10.1080/08037051.2019.1633907] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Ulla Hjørnholm
- Section of Cardiovascular and Renal Research, Oslo University Hospital, Oslo, Norway
- Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Anne Cecilie K. Larstorp
- Section of Cardiovascular and Renal Research, Oslo University Hospital, Oslo, Norway
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marit Helen Andersen
- Institute of Health and Society, University of Oslo, Oslo, Norway
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Aud Høieggen
- Section of Cardiovascular and Renal Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Nephrology, Oslo University Hospital, Oslo, Norway
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38
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Pelouch R, Voříšek V, Furmanová V, Solař M. The Assessment of Serum Drug Levels to Diagnose Non-Adherence in Stable Chronic Heart Failure Patients. ACTA MEDICA (HRADEC KRÁLOVÉ) 2019; 62:52-57. [DOI: 10.14712/18059694.2019.46] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Background: The aim of our study was to evaluate the prevalence of drug non-adherence in stable chronic heart failure (CHF) patients using serum drug levels (SDL) assessment. Methods: CHF patients were prospectively enrolled during scheduled outpatient visit. Except standard procedures an unanticipated blood sampling for the SDL assessment was obtained. Analysis was focused on the prescribed heart failure and antihypertensive medication and was performed by liquid chromatography coupled with mass spectrometry. The patient was labelled as non-adherent if at least one of drugs assessed was not found in the serum. In the first half of patients multiple SDL have been evaluated during the follow-up. Results: Eighty one patients were enrolled. The non-adherence was proven in twenty of them (25%). In the subgroup of thirty eight patients with multiple SDL evaluation the non-adherence raised significantly with increasing number of visits assessed together (21% for single visit, 29% for two of three visits assessed together and 34% for all three visits evaluated together, all p < 0.001). Conclusion: The non-adherence was proven in significant part of stable CHF patients using SDL assessment. This method seems to be reliable and effective and should be a part of clinical assessment in selected patients with CHF.
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Richter LHJ, Jacobs CM, Mahfoud F, Kindermann I, Böhm M, Meyer MR. Development and application of a LC-HRMS/MS method for analyzing antihypertensive drugs in oral fluid for monitoring drug adherence. Anal Chim Acta 2019; 1070:69-79. [PMID: 31103169 DOI: 10.1016/j.aca.2019.04.026] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 04/11/2019] [Indexed: 10/27/2022]
Abstract
Nonadherence to antihypertensive drugs therapy is known to be a serious issue in hypertension treatment. Liquid chromatography (LC) coupled to mass spectrometry (MS) was shown to allow the assessment of such nonadherence in blood and urine sample. However, their sampling may represent a logistical challenge and are often not favored by the patients. We questioned whether oral fluid (OF) might be an easier accessible alternative matrix for adherence monitoring of cardiovascular drugs (CD). A qualitative method for adherence monitoring of 78 commonly prescribed cardiovascular drugs in OF using LC high-resolution MS (LC-HRMS/MS) was therefore developed, validated, and used to study the presence of antihypertensive medication in OF. Selectivity, ion suppression and enhancement due coeluting analytes, carry over, limits of detection (LOD), limits of identification (LOI), recovery (RE), matrix effects (ME), and process efficiency (PE) were investigated. For demonstrating applicability, over 50 OF samples were investigated and data were compared to findings in blood and urine. Selectivity in OF was given for all compounds via their MS2 spectra and no total suppression of signals could be observed. Determined LOI in OF for ten analytes was higher than the given therapeutic plasma concentration. Furthermore, RE, ME, and PE were in acceptable ranges for more than 65% of the compounds. In total, 208 prescriptions of CD to 57 patients were analyzed and demonstrated the suitability of for adherence monitoring in principle. OF was comparable to plasma regarding the drug categories and the frequencies of hits, except for acidic compounds but more hits could be found in urine samples. A analytical method using OF as analytical matrix was successfully developed. Application showed that it might be a suitable alternative for adherence monitoring of selected drugs in the future, particularly those having no acidic function.
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Affiliation(s)
- Lilian H J Richter
- Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421, Homburg, Germany
| | - Cathy M Jacobs
- Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421, Homburg, Germany
| | - Felix Mahfoud
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Saarland University, Homburg, Germany
| | - Ingrid Kindermann
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Saarland University, Homburg, Germany
| | - Michael Böhm
- Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Saarland University, Homburg, Germany
| | - Markus R Meyer
- Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421, Homburg, Germany.
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40
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Wunder C, Persu A, Lengelé JP, Mg Georges C, Renkin J, Pasquet A, Carlier M, Zhang ZY, Staessen JA. Adherence to antihypertensive drug treatment in patients with apparently treatment-resistant hypertension in the INSPiRED pilot study. Blood Press 2019; 28:168-172. [PMID: 30942111 DOI: 10.1080/08037051.2019.1599814] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
PURPOSE Drug adherence may be a major problem in the therapy of hypertension and in the diagnosis of therapy resistance. Adherence can be assessed by indirect methods or by direct methods like drug detection in urine with liquid chromatography-mass spectrometric methods. MATERIALS AND METHODS The current analysis included patients with apparently treatment- resistant hypertension (TRH) referred for renal denervation (RDN) and included in the the INSPiRED pilot trial (NCT01505010). Adherence was repeatedly assessed by toxicological urine analysis over a time range of up to 17 months in a total of 18 patients. RESULTS In the first urine samples of 18 patients the adherence rate (percentage of number of detected vs. prescribed medical drugs) ranged from 0 to 100% with a median of 73.2%. In further urine samples collected during the following up to 17 months every individual patient exhibited considerable changes in the adherence rate, neither a constancy nor a tendency could be deduced. CONCLUSIONS Urine analysis results exhibit variation over time and an assessment at a certain time point cannot be regarded as representative or predictor for future behavior. Therefore, it appears necessary to perform drug adherence testing repeatedly over time.
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Affiliation(s)
- Cora Wunder
- a Institute of Legal Medicine, Goethe-University Frankfurt , Frankfurt , Germany
| | - Alexandre Persu
- b Division of Cardiology , Cliniques Universitaires Saint-Luc, Université Catholique de Louvain , Brussels , Belgium.,c Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique , Université Catholique de Louvain , Brussels , Belgium
| | - Jean-Philippe Lengelé
- b Division of Cardiology , Cliniques Universitaires Saint-Luc, Université Catholique de Louvain , Brussels , Belgium.,d Department of Nephrology , Grand Hôpital de Charleroi , Gilly , Belgium
| | - Coralie Mg Georges
- b Division of Cardiology , Cliniques Universitaires Saint-Luc, Université Catholique de Louvain , Brussels , Belgium
| | - Jean Renkin
- b Division of Cardiology , Cliniques Universitaires Saint-Luc, Université Catholique de Louvain , Brussels , Belgium.,c Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique , Université Catholique de Louvain , Brussels , Belgium
| | - Agnès Pasquet
- b Division of Cardiology , Cliniques Universitaires Saint-Luc, Université Catholique de Louvain , Brussels , Belgium
| | - Marc Carlier
- e Department of Cardiology , Grand Hôpital de Charleroi , Gilly , Belgium
| | - Zhen-Yu Zhang
- f Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences , University of Leuven , Leuven , Belgium
| | - Jan A Staessen
- f Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences , University of Leuven , Leuven , Belgium.,g Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht , The Netherlands
| | -
- a Institute of Legal Medicine, Goethe-University Frankfurt , Frankfurt , Germany
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41
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Hameed MA, Dasgupta I. Medication adherence and treatment-resistant hypertension: a review. Drugs Context 2019; 8:212560. [PMID: 30774692 PMCID: PMC6365088 DOI: 10.7573/dic.212560] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/28/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022] Open
Abstract
Nonadherence is a common reason for treatment failure and treatment resistance. No matter how it is defined, it is a major issue in the management of chronic illnesses. There are numerous methods to assess adherence, each with its own strengths and weaknesses; however, no single method is considered the best. Nonadherence is common in patients with hypertension, and it is present in a large proportion of patients with uncontrolled blood pressure taking three or more antihypertensive agents. Availability of procedure-based treatment options for these patients has shed further light on this important issue with development of new methods to assess adherence. There is, however, no consensus on the management of nonadherence, which reflects the complex interplay of factors responsible for it.
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Affiliation(s)
- Mohammed Awais Hameed
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK.,University Hospitals Birmingham NHS Foundation Trust, Birmingham Heartlands Hospital, Birmingham, UK
| | - Indranil Dasgupta
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK.,University Hospitals Birmingham NHS Foundation Trust, Birmingham Heartlands Hospital, Birmingham, UK
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42
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Burns AD, Lane D, Cole R, Patel P, Gupta P. Cardiovascular Medication Stability in Urine for Non-Adherence Screening by LC–MS-MS. J Anal Toxicol 2018; 43:325-329. [DOI: 10.1093/jat/bky090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 09/21/2018] [Indexed: 12/20/2022] Open
Affiliation(s)
- A D Burns
- Department of Chemical Pathology and Metabolic Diseases, Level 4, Sandringham Building, Leicester Royal Infirmary, UK
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - D Lane
- Department of Chemical Pathology and Metabolic Diseases, Level 4, Sandringham Building, Leicester Royal Infirmary, UK
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | | | - P Patel
- Department of Chemical Pathology and Metabolic Diseases, Level 4, Sandringham Building, Leicester Royal Infirmary, UK
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - P Gupta
- Department of Chemical Pathology and Metabolic Diseases, Level 4, Sandringham Building, Leicester Royal Infirmary, UK
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
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43
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van Schoonhoven AV, van Asselt AD, Tomaszewski M, Patel P, Khunti K, Gupta P, Postma MJ. Cost-Utility of an Objective Biochemical Measure to Improve Adherence to Antihypertensive Treatment. Hypertension 2018; 72:1117-1124. [DOI: 10.1161/hypertensionaha.118.11227] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Alexander V. van Schoonhoven
- From the Unit of PharmacoTherapy, -Epidemiology, and -Economics, Department of Pharmacy, University of Groningen, The Netherlands (A.V.v.S., A.D.I.v.A., M.J.P.)
| | - Antoinette D.I. van Asselt
- From the Unit of PharmacoTherapy, -Epidemiology, and -Economics, Department of Pharmacy, University of Groningen, The Netherlands (A.V.v.S., A.D.I.v.A., M.J.P.)
- Department of Epidemiology, University Medical Centre Groningen, University of Groningen, The Netherlands (A.D.I.v.A., M.J.P.)
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, United Kingdom (M.T., P.G.)
- Division of Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom (M.T.)
| | - Prashanth Patel
- Department of Chemical Pathology and Metabolic Diseases, University Hospitals of Leicester NHS Trust, United Kingdom (P.P., P.G.)
- Department of Cardiovascular Sciences, British Heart Foundation Cardiovascular Research Centre, University of Leicester, United Kingdom (P.P., P.G.)
| | - Kamlesh Khunti
- Department of Cardiovascular Sciences, British Heart Foundation Cardiovascular Research Centre, University of Leicester, United Kingdom (P.P., P.G.)
| | - Pankaj Gupta
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, United Kingdom (M.T., P.G.)
- Department of Chemical Pathology and Metabolic Diseases, University Hospitals of Leicester NHS Trust, United Kingdom (P.P., P.G.)
- Department of Cardiovascular Sciences, British Heart Foundation Cardiovascular Research Centre, University of Leicester, United Kingdom (P.P., P.G.)
| | - Maarten J. Postma
- From the Unit of PharmacoTherapy, -Epidemiology, and -Economics, Department of Pharmacy, University of Groningen, The Netherlands (A.V.v.S., A.D.I.v.A., M.J.P.)
- Department of Epidemiology, University Medical Centre Groningen, University of Groningen, The Netherlands (A.D.I.v.A., M.J.P.)
- Department of Health Sciences, University Medical Centre Groningen, University of Groningen, The Netherlands (M.J.P.)
- Department of Economics, Econometrics and Finance, University of Groningen, Faculty of Economics and Business, The Netherlands (M.J.P.)
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44
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Attenuation of hypertension by C-fiber stimulation of the human median nerve and the concept-based novel device. Sci Rep 2018; 8:14967. [PMID: 30297735 PMCID: PMC6175881 DOI: 10.1038/s41598-018-33402-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/26/2018] [Indexed: 11/09/2022] Open
Abstract
High blood pressure (BP) is a highly controllable risk factor for cardiovascular diseases; however, awareness of this condition and the rates of controlled hypertension are low. Experimental animal studies have shown that stimulation of the median nerve or PC6 acupoint over the wrist has effects on cardiovascular activities, including reductions in systolic and diastolic BPs. A proof-of-concept study was conducted in humans to investigate whether stimulation of median nerve near PC6 acupoint decreased high BP, identify the optimal stimulation parameters for the BP-lowering effects of median nerve stimulation, and determine the specific peripheral nerves or types of afferent fibers mediating the BP-lowering effects. Median nerve stimulation was carried out bilaterally or unilaterally with different stimulation parameters, and the BP and heart rate were monitored. The afferent mechanisms underlying the effects of median nerve stimulation on hypertension were investigated via microneurography, A-fiber blocking experiments, and localized chemical or electrical stimulation. Bilateral median nerve stimulation at either low or high frequencies produced profound but transient reductions in systolic BP, which were elicited when median nerve stimulation was unilaterally applied at interelectrode distances of 2 and 4 cm. Systolic BP was also reduced by electrical stimulation of the thumb on the palm side. Although microneurographic recordings revealed the excitation of both A- and C-fibers following median nerve stimulation, the median nerve-mediated reductions in BP were not affected by A-fiber blockade, and they were mimicked by the activation of C-fibers with capsaicin. The present results indicate that activation of C-fibers in the median nerve generates BP-lowering effects in humans. Based on our clinical study, an optimized median nerve stimulator was built and combined with a wrist BP monitor for simultaneous BP measurements and median nerve stimulation.
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Abstract
PURPOSE OF REVIEW Recent US guidelines have changed the definition of hypertension to ≥ 130/80 mmHg and recommended more intense blood pressure (BP) targets. We summarize the evidence for intense BP treatment and discuss risks that must be considered when choosing treatment goals for individual patients. RECENT FINDINGS The SPRINT study reported that treating to a systolic BP target of 120 mmHg reduces cardiovascular outcomes in high-risk individuals, supporting more intensive BP reduction than previously recommended. However, recent observational studies have placed emphasis on the BP J-curve phenomenon, where low BPs are associated with adverse cardiovascular outcomes, suggesting that overly aggressive BP targets may sometimes be harmful. We attempt to reconcile these apparent contradictions for the clinician. We also review other potential dangers of aggressive BP targets, including syncope, renal impairment, polypharmacy, drug interactions, subjective drug side-effects, and non-adherence. We suggest a personalized approach to BP drug management considering individual risks, benefits, and preferences when choosing therapeutic targets, recognizing that a goal of 130/80 mmHg should always be considered. Additionally, we recommend an intense focus on lifestyle changes and medication adherence.
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46
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Courand PY, Azizi M, Lantelme P. Renal denervation in hypertension: Towards a true revival? Arch Cardiovasc Dis 2018; 111:541-544. [PMID: 30219622 DOI: 10.1016/j.acvd.2018.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 08/17/2018] [Indexed: 11/27/2022]
Affiliation(s)
- Pierre-Yves Courand
- Cardiology Department, European Society of Hypertension Excellence Centre, hôpital de la Croix-Rousse et hôpital Lyon Sud, hospices civils de Lyon, 69004 Lyon, France; CREATIS, CNRS UMR 5220, INSERM U1044, INSA-Lyon, université Claude-Bernard Lyon 1, hospices civils de Lyon, 69100 Lyon, France.
| | - Michel Azizi
- Université Paris-Descartes, 75006 Paris, France; Hypertension Department, hôpital européen Georges-Pompidou, AP-HP, 75908 Paris, France; INSERM CIC 1418, 75908 Paris, France
| | - Pierre Lantelme
- Cardiology Department, European Society of Hypertension Excellence Centre, hôpital de la Croix-Rousse et hôpital Lyon Sud, hospices civils de Lyon, 69004 Lyon, France; CREATIS, CNRS UMR 5220, INSERM U1044, INSA-Lyon, université Claude-Bernard Lyon 1, hospices civils de Lyon, 69100 Lyon, France
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47
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Avataneo V, De Nicolò A, Rabbia F, Perlo E, Burrello J, Berra E, Pappaccogli M, Cusato J, D'Avolio A, Di Perri G, Veglio F. Therapeutic drug monitoring-guided definition of adherence profiles in resistant hypertension and identification of predictors of poor adherence. Br J Clin Pharmacol 2018; 84:2535-2543. [PMID: 29971815 DOI: 10.1111/bcp.13706] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 06/01/2018] [Accepted: 06/23/2018] [Indexed: 12/11/2022] Open
Abstract
AIMS Arterial hypertension is an important cardiovascular risk factor. A substantial proportion of patients show resistance to antihypertensive treatment but poor adherence to medication regimens is also a significant cause of treatment failure. In this context, therapeutic drug monitoring (TDM) could be useful. The objective of this study was to assess adherence to treatment in patients with resistant hypertension by TDM and to identify parameters that predict nonadherence. METHODS Liquid chromatography tandem mass spectrometry was used to quantify a wide panel of antihypertensive drugs in human plasma to assess treatment compliance. Associations between TDM-determined adherence profiles, self-reported adherence and other patient-related clinical, anthropometric or demographic features were evaluated as potentially useful pre-TDM predictors of poor adherence. RESULTS TDM was performed on 50 patients with suspected resistant hypertension: 24% of patients partially complied to treatment and 18% were nonadherent. No concordance was observed with questionnaire results, while nonadherence was associated with high diastolic blood pressure, high heart rate, previous onset of stroke and previous use of invasive treatments, including renal denervation or baroreceptor stimulation. CONCLUSIONS This evidence highlights the high prevalence of poor adherence in patients with resistant hypertension and the need for caution in using invasive approaches. These preliminary data require validation in a larger cohort, to confirm the need for TDM in routine clinical practice.
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Affiliation(s)
- Valeria Avataneo
- Laboratory of Clinical Pharmacology and Pharmacogenetics#, University of Turin, Turin, Italy.,Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Amedeo De Nicolò
- Laboratory of Clinical Pharmacology and Pharmacogenetics#, University of Turin, Turin, Italy.,Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Franco Rabbia
- Division of Internal Medicine and Hypertension Unit, University of Turin, Turin, Italy.,Department of Medical Sciences, AOU Città della Salute e della Scienza, Turin, Italy
| | - Elisa Perlo
- Division of Internal Medicine and Hypertension Unit, University of Turin, Turin, Italy.,Department of Medical Sciences, AOU Città della Salute e della Scienza, Turin, Italy
| | - Jacopo Burrello
- Division of Internal Medicine and Hypertension Unit, University of Turin, Turin, Italy.,Department of Medical Sciences, AOU Città della Salute e della Scienza, Turin, Italy
| | - Elena Berra
- Division of Internal Medicine and Hypertension Unit, University of Turin, Turin, Italy.,Department of Medical Sciences, AOU Città della Salute e della Scienza, Turin, Italy
| | - Marco Pappaccogli
- Division of Internal Medicine and Hypertension Unit, University of Turin, Turin, Italy.,Department of Medical Sciences, AOU Città della Salute e della Scienza, Turin, Italy
| | - Jessica Cusato
- Laboratory of Clinical Pharmacology and Pharmacogenetics#, University of Turin, Turin, Italy.,Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Antonio D'Avolio
- Laboratory of Clinical Pharmacology and Pharmacogenetics#, University of Turin, Turin, Italy.,Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Giovanni Di Perri
- Laboratory of Clinical Pharmacology and Pharmacogenetics#, University of Turin, Turin, Italy.,Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
| | - Franco Veglio
- Division of Internal Medicine and Hypertension Unit, University of Turin, Turin, Italy.,Department of Medical Sciences, AOU Città della Salute e della Scienza, Turin, Italy
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48
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Laius O, Pisarev H, Volmer D, Kõks S, Märtson A, Maasalu K. Use of a national database as a tool to identify primary medication non-adherence: The Estonian ePrescription system. Res Social Adm Pharm 2018; 14:776-783. [DOI: 10.1016/j.sapharm.2017.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/04/2017] [Accepted: 10/04/2017] [Indexed: 11/26/2022]
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49
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Quantification of 21 antihypertensive drugs in serum using UHPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1089:84-93. [DOI: 10.1016/j.jchromb.2018.04.038] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 04/16/2018] [Accepted: 04/22/2018] [Indexed: 12/17/2022]
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50
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Indexed plasma drug concentrations for drug adherence screening in hypertensive patients. Ann Cardiol Angeiol (Paris) 2018; 67:119-126. [PMID: 29789122 DOI: 10.1016/j.ancard.2018.04.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 04/27/2018] [Indexed: 11/20/2022]
Abstract
AIM Due to its high sensitivity, qualitative plasma drug screening by liquid chromatography/tandem mass spectrometry may not be able to distinguish same-day drug intake from drug use on preceding days and cause misclassifications of drug adherence in hypertensive patients. Analysis of plasma drug concentrations may provide more accurate results. PATIENTS AND METHODS We describe dose-dependent indexing of plasma drug concentrations for expected peak concentrations to define individual screening thresholds for same-day drug use. To explore its utility, plasma samples from 9 hypertensive patients without major comorbidity were prospectively analyzed on two occasions. All were on hydrochlorothiazide with either amlodipine (n=7) and/or valsartan (n=6) at different doses. Drugs were quantitated by mass spectrometry. Non-adherence was defined if an indexed drug concentration was below the expected trough level at 24-hour dosing interval. RESULTS All patients were adherent by qualitative plasma screening (spectrometric sensitivity). On the first visit (random sampling time), mean plasma concentrations of the drugs were 102±70, 15.4±6.7 and 2529±1608ng/mL, and mean indexes 84±57%, 85±35% and 60±38%, respectively. Using the study criterion, non-adherence was suspected in three. Intraindividual cross-checking retained two. On the second visit (fixed sampling time), amlodipine concentration was 15.6±8.5ng/mL (88±52% after indexing). Two patients were non-adherent according to the study criterion. CONCLUSION Indexing of plasma drug concentrations appears practicable and useful for drug adherence screening under clinical conditions. With this technique, same-day drug intake can be easily distinguished which reduces the risk of false positive results associated with qualitative drug screening.
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