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      Urinary drug metabolite testing in chronic heart failure patients indicates high levels of adherence with life‐prolonging therapies

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          Abstract

          Aims

          Despite medical therapy for heart failure (HF) having proven benefits of improving quality of life and survival, many patients remain under‐treated. This may be due to a combination of under‐prescription by medical professionals and poor adherence from patients. In HF, as with many other chronic diseases, adherence to medication can deteriorate over time particularly when symptoms are well controlled. Therefore, detecting and addressing non‐adherence has a crucial role in the management of HF. Significant flaws and inaccuracies exist in the methods currently used to assess adherence such as patient reporting, pill counts, and pharmacy fill records. We aim to use high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS) to detect metabolites of HF medications in the urine samples of chronic HF patients.

          Methods and results

          Urine samples were collected from 35 patients in a specialist HF clinic. Patients were included if they had an ejection fraction <45% and were taking at least two disease‐modifying HF medications. They were excluded if they had been admitted to hospital for HF in the 3 months preceding clinic attendance. These samples were sent for HPLC‐MS and tested for all HF medications prescribed for that patient. A high rate of complete adherence of 89% was detected in these patients, with 94% being partially adherent (at least one HF medication detected) to therapy (at least one HF medication detected). This analysis also highlighted that mineralocorticoid antagonists represent both the most under‐prescribed (67%) and poorly adhered (75%) medication class.

          Conclusions

          This analysis revealed a surprisingly high level of adherence to disease‐modifying therapy in chronic HF patients and highlights that most of our ‘total’ under‐treatment is likely to be from a failure to prescribe rather than a failure to adhere. Testing for metabolites of disease‐modifying HF drugs in urine using HPLC‐MS is feasible and is a useful adjunct to a specialist HF service. At present, the distinction between treatment failure and failure to take treatment is not always clear, which is important because the investigation and potential solutions are different. The former needs initiation of additional therapies and consideration of additional diagnoses, whereas the latter requires strategies to understand reasons underlying poor adherence and collaborative working to improve this: the wrong strategy will be ineffective.

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          Most cited references9

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          Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories.

          To describe characteristics of dosing history in patients prescribed a once a day antihypertensive medication. Longitudinal database study. Clinical studies archived in database for 1989-2006. Patients who participated in the studies whose dosing histories were available through electronic monitoring. Persistence with prescribed antihypertensive treatment and execution of their once a day drug dosing regimens. The database contained dosing histories of 4783 patients with hypertension. The data came from 21 phase IV clinical studies, with lengths ranging from 30 to 330 days and involving 43 different antihypertensive drugs, including angiotensin II receptor blockers (n=2088), calcium channel blockers (n=937), angiotensin converting enzyme inhibitors (n=665), beta blockers (n=195), and diuretics (n=155). About half of the patients who were prescribed an antihypertensive drug had stopped taking it within one year. On any day, patients who were still engaged with the drug dosing regimen omitted about 10% of the scheduled doses: 42% of these omissions were of a single day's dose, whereas 43% were part of a sequence of several days (three or more days-that is, drug "holidays"). Almost half of the patients had at least one drug holiday a year. The likelihood that a patient would discontinue treatment early was inversely related to the quality of his or her daily execution of the dosing regimen. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimens are the most common facets of poor adherence with once a day antihypertensive drug treatments. The shortfalls in drug exposure that these dosing errors create might be a common cause of low rates of blood pressure control and high variability in responses to prescribed antihypertensive drugs.
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            Impact of medication nonadherence on hospitalizations and mortality in heart failure.

            Limited literature exists on the association between medication adherence and outcomes among patients with heart failure. We conducted a retrospective longitudinal cohort study of 557 patients with heart failure with reduced ejection fraction (HFrEF) (defined by EF <50%) in a large health maintenance organization. We used multivariable Cox proportional hazards models to assess the relationship between adherence (with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, and aldosterone antagonists) and the primary outcome of all-cause mortality plus cardiovascular hospitalizations. Mean follow-up time was 1.1 years. Nonadherence (defined as <80% adherence) was associated with a statistically significant increase in the primary outcome in the cohort overall (hazard ratio 2.07, 95% confidence interval 1.62-2.64; P < .0001). This association remained significant when all 3 classes of heart failure medications and the components of the composite end point were considered separately and when the adherence threshold was varied to 70% or 90%. Medication nonadherence was associated with an increased risk of all-cause mortality and cardiovascular hospitalizations in a community heart failure population. Further research is needed to define systems of care that optimize adherence among patients with heart failure. Copyright © 2011 Elsevier Inc. All rights reserved.
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              High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis

              Objectives Non-adherence to therapy is an important cause of suboptimal blood pressure control but few practical tools exist to accurately and routinely detect it. We used a simple urine-based assay to evaluate the prevalence of antihypertensive treatment non-adherence and its impact on blood pressure in a specialist hypertension centre. Methods 208 hypertensive patients (125 new referrals, 66 follow-up patients with inadequate blood pressure control and 17 renal denervation referrals) underwent assessment of antihypertensive drug intake using high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis at the time of clinical appointment. A total of 40 most commonly prescribed antihypertensive medications (or their metabolites) were screened for in spot urine samples. Results Overall, 25% of patients were totally or partially non-adherent to antihypertensive treatment (total non-adherence 10.1%, partial non-adherence 14.9%). The highest prevalence of partial and total non-adherence was among follow-up patients with inadequate blood pressure control (28.8%) and those referred for consideration of renal denervation (23.5%), respectively. There was a linear relationship between blood pressure and the numerical difference in detected/prescribed antihypertensive medications—every unit increase in this difference was associated with 3.0 (1.1) mm Hg, 3.1 (0.7) mm Hg and 1.9 (0.7) mm Hg increase in adjusted clinic systolic blood pressure, clinic diastolic blood pressure (DBP) and 24 h mean daytime DBP (p=0.0051, p=8.62×10−6, p=0.0057), respectively. Conclusions Non-adherence to blood pressure lowering therapy is common, particularly in patients with suboptimal blood pressure control and those referred for renal denervation. HP LC-MS/MS urine analysis could be used to exclude non-adherence and better stratify further investigations and intervention.
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                Author and article information

                Contributors
                graham.cole3@nhs.net
                Journal
                ESC Heart Fail
                ESC Heart Fail
                10.1002/(ISSN)2055-5822
                EHF2
                ESC Heart Failure
                John Wiley and Sons Inc. (Hoboken )
                2055-5822
                11 March 2021
                June 2021
                : 8
                : 3 ( doiID: 10.1002/ehf2.v8.3 )
                : 2334-2337
                Affiliations
                [ 1 ] Imperial College Healthcare NHS Trust London UK
                [ 2 ] Imperial College London London UK
                Author notes
                [*] [* ]Correspondence to: Dr Graham D. Cole, National Heart and Lung Institute, Imperial College London, 2nd Floor B Block, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK. Tel: 02033131000. Email: graham.cole3@ 123456nhs.net
                Article
                EHF213284 ESCHF-21-00033
                10.1002/ehf2.13284
                8120374
                33709563
                d19f0f73-222e-4c9a-9582-4bd65ea15071
                © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 January 2021
                : 15 February 2021
                Page count
                Figures: 1, Tables: 1, Pages: 4, Words: 1535
                Funding
                Funded by: Nissan Cardiology Charitable Fund
                Funded by: NIHR Imperial Biomedical Research Centre (BRC) , open-funder-registry 10.13039/501100013342;
                Funded by: Wellcome Trust , open-funder-registry 10.13039/100010269;
                Award ID: 220573/Z/20/Z
                Categories
                Short Communication
                Short Communications
                Custom metadata
                2.0
                June 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:14.05.2021

                heart failure,ace inhibitor,beta‐blocker,aldosterone antagonist,adherence,urinary testing

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