We hypothesized that screening for nonadherence to antihypertensive treatment using liquid chromatography-tandem mass spectrometry-based biochemical analysis of urine/serum has therapeutic applications in nonadherent hypertensive patients. A retrospective analysis of hypertensive patients attending specialist tertiary care centers was conducted in 2 European countries (United Kingdom and Czech Republic). Nonadherence to antihypertensive treatment was diagnosed using biochemical analysis of urine (United Kingdom) or serum (Czech Republic). These results were subsequently discussed with each patient, and data on follow-up clinic blood pressure (BP) measurements were collected from clinical files. Of 238 UK patients who underwent biochemical urine analysis, 73 were nonadherent to antihypertensive treatment. Their initial urinary adherence ratio (the ratio of detected to prescribed antihypertensive medications) increased from 0.33 (0-0.67) to 1 (0.67-1) between the first and the last clinic appointments. The observed increase in the urinary adherence ratio in initially nonadherent UK patients was associated with the improved BP control; by the last clinic appointment, systolic and diastolic BPs were ≈19.5 and 7.5 mm Hg lower than at baseline (P=0.001 and 0.009, respectively). These findings were further corroborated in 93 nonadherent hypertensive patients from Czech Republic-their average systolic and diastolic BPs dropped by ≈32.6 and 17.4 mm Hg, respectively (P<0.001), on appointments after the biochemical analysis. Our data show that nonadherent hypertensive patients respond to liquid chromatography-tandem mass spectrometry-based biochemical analysis with improved adherence and significant BP drop. Such repeated biochemical analyses should be considered as a therapeutic approach in nonadherent hypertensive patients.

From the Department of Metabolic Medicine and Chemical Pathology University Hospitals of Leicester NHS Trust United Kingdom

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WHO. A global brief on hypertension. who.int/cardiovascular_diseases/publications/global_brief_hypertension. Accessed January 16, 2017.

Neal B, MacMahon S, Chapman N Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2000;356:1955–1964. PubMed

Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, Jones DW, Materson BJ, Oparil S, Wright JT, Jr, Roccella EJ National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–2572. doi: 10.1001/jama.289.19.2560. PubMed

Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. PubMed PMC

Kotseva K, Wood D, De Bacquer D, et al. EUROASPIRE Investigators. EUROASPIRE IV: a European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prev Cardiol. 2016;23:636–648. doi: 10.1177/2047487315569401. PubMed

Yoon S, Fryar C, Carroll M. Hyattsville, MD: National Center for Health Statistics; Hypertension prevalence and control among adults: United States, 2011–2014. NCHS Data Brief, no 220. www.cdc.gov/nchs/data/databriefs/db220.htm. Accessed December 18, 2016. PubMed

Corrao G, Zambon A, Parodi A, Poluzzi E, Baldi I, Merlino L, Cesana G, Mancia G. Discontinuation of and changes in drug therapy for hypertension among newly-treated patients: a population-based study in Italy. J Hypertens. 2008;26:819–824. doi: 10.1097/HJH.0b013e3282f4edd7. PubMed

Jung O, Gechter JL, Wunder C, Paulke A, Bartel C, Geiger H, Toennes SW. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens. 2013;31:766–774. doi: 10.1097/HJH.0b013e32835e2286. PubMed

Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, Stricker B, Mendis S, Hofman A, Mant J, Franco OH. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J. 2013;34:2940–2948. doi: 10.1093/eurheartj/eht295. PubMed

Tomaszewski M, White C, Patel P, Masca N, Damani R, Hepworth J, Samani NJ, Gupta P, Madira W, Stanley A, Williams B. High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart. 2014;100:855–861. doi: 10.1136/heartjnl-2013-305063. PubMed PMC

Ceral J, Habrdova V, Vorisek V, Bima M, Pelouch R, Solar M. Difficult-to-control arterial hypertension or uncooperative patients? The assessment of serum antihypertensive drug levels to differentiate non-responsiveness from non-adherence to recommended therapy. Hypertens Res. 2011;34:87–90. doi: 10.1038/hr.2010.183. PubMed

Strauch B, Petrák O, Zelinka T, Rosa J, Somlóová Z, Indra T, Chytil L, Marešová V, Kurcová I, Holaj R, Wichterle D, Widimský J., Jr Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis. J Hypertens. 2013;31:2455–2461. doi: 10.1097/HJH.0b013e3283652c61. PubMed

Brinker S, Pandey A, Ayers C, Price A, Raheja P, Arbique D, Das SR, Halm EA, Kaplan NM, Vongpatanasin W. Therapeutic drug monitoring facilitates blood pressure control in resistant hypertension. J Am Coll Cardiol. 2014;63:834–835. doi: 10.1016/j.jacc.2013.10.067. PubMed PMC

Rosa J, Zelinka T, Petrák O, Štrauch B, Šomlóová Z, Indra T, Holaj R, Čurila K, Toušek P, Šenitko M, Widimský P, Widimský J., Jr Importance of thorough investigation of resistant hypertension before renal denervation: should compliance to treatment be evaluated systematically? J Hum Hypertens. 2014;28:684–688. doi: 10.1038/jhh.2014.3. PubMed

Ewen S, Meyer MR, Cremers B, Laufs U, Helfer AG, Linz D, Kindermann I, Ukena C, Burnier M, Wagenpfeil S, Maurer HH, Böhm M, Mahfoud F. Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis. Clin Res Cardiol. 2015;104:1097–1105. doi: 10.1007/s00392-015-0905-5. PubMed

Pandey A, Raza F, Velasco A, Brinker S, Ayers C, Das SR, Morisky DE, Halm EA, Vongpatanasin W. Comparison of Morisky Medication Adherence Scale with therapeutic drug monitoring in apparent treatment-resistant hypertension. J Am Soc Hypertens. 2015;9:420–426.e2. doi: 10.1016/j.jash.2015.04.004. PubMed

Patel P, Gupta PK, White CM, Stanley AG, Williams B, Tomaszewski M. Screening for non-adherence to antihypertensive treatment as a part of the diagnostic pathway to renal denervation. J Hum Hypertens. 2016;30:368–373. doi: 10.1038/jhh.2015.103. PubMed PMC

Schmieder RE, Ott C, Schmid A, Friedrich S, Kistner I, Ditting T, Veelken R, Uder M, Toennes SW. Adherence to antihypertensive medication in treatment-resistant hypertension undergoing renal denervation. J Am Heart Assoc. 2016;5:e002343. doi: 10.1161/JAHA.115.002343. PubMed PMC

Gupta P, Patel P, Štrauch B, et al. Risk factors for nonadherence to antihypertensive treatment. Hypertension. 2017;69:1113–1120. doi: 10.1161/HYPERTENSIONAHA.116.08729. PubMed

NICE. CG127 hypertension: clinical management of primary hypertension in adults. www.nice.org.uk/CG127. Accessed February 16, 2017.

Filipovský J, Widimský J, Jr, Ceral J, Cífková R, Horký K, Linhart A, Monhart V, Rosolová H, Seidlerová J, Souček M, Špinar J, Vítovec J, Widimský J. Diagnostické a léčebné postupy u arteriální hypertenze – verze 2012. Doporučení české společnosti pro hypertenzi. Hypertenze a kardiovaskulární prevence. 2012;3:1–16. PubMed

Chytil L, Cvačka J, Marešová V, Štrauch B, Widimský J, Jr, Štícha M, Slanař O. Development of a fast LC-MS/MS method for quantification of rilmenidine in human serum: elucidation of fragmentation pathways by HRMS. J Mass Spectrom. 2010;45:1179–1185. doi: 10.1002/jms.1809. PubMed

Iriarte G, Gonzalez O, Ferreirós N, Maguregui MI, Alonso RM, Jiménez RM. Validation of a fast liquid chromatography-UV method for the analysis of drugs used in combined cardiovascular therapy in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:3045–3053. doi: 10.1016/j.jchromb.2009.07.018. PubMed

Chytil L, Strauch B, Cvačka J, Marešová V, Widimský J, Jr, Holaj R, Slanař O. Determination of doxazosin and verapamil in human serum by fast LC-MS/MS: application to document non-compliance of patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:3167–3173. doi: 10.1016/j.jchromb.2010.09.032. PubMed

Florczak E, Tokarczyk B, Warchoł-Celińska E, Szwench-Pietrasz E, Prejbisz A, Gosk M, Kabat M, Narkiewicz K, Januszewicz A, Kała M. Assessment of adherence to treatment in patients with resistant hypertension using toxicological serum analysis. A subgroup evaluation of the RESIST-POL study. Pol Arch Med Wewn. 2015;125:65–72. PubMed

Nakagawa S, Schielzeth H. A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods Ecol Evol. 2013;4:133–142.

R Core Team A Language and Environment for Statistical Computing. Vienna, Austria:: R Foundation for Statistical Computing; . https://www.R-project.org. Accessed December 12, 2016.

Bates D, Maechler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67:1–42.

Dowle M, Srinivasan A, Short T, Lianoglou S with contributions from Saporta R, Antonyan E. data.table: extension of Data frame. R package version 1.9.6.2015. https://CRAN.R-project.org/package=data.table Accessed October 06, 2016.

Wickham H, editor. Elegant Graphics for Data Analysis. New York, NY: Springer-Verlag; 2009.

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117:e510–e526. doi: 10.1161/CIRCULATIONAHA.108.189141. PubMed

Horne R, Chapman SC, Parham R, Freemantle N, Forbes A, Cooper V. Understanding patients’ adherence-related beliefs about medicines prescribed for long-term conditions: a meta-analytic review of the Necessity-Concerns Framework. PLoS One. 2013;8:e80633. doi: 10.1371/journal.pone.0080633. PubMed PMC

WHO. Adherence to long-term therapies: evidence for action. www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Accessed December 12, 2016.

NICE. NICE Clinical Guideline 76: medicines adherence. www.nice.org.uk/CG76. Accessed April 5, 2017.

Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326:1427. doi: 10.1136/bmj.326.7404.1427. PubMed PMC

Schroeder K, Fahey T, Ebrahim S. Interventions for improving adherence to treatment in patients with high blood pressure in ambulatory settings. Cochrane Database Syst Rev. 2004;2:CD004804. PubMed PMC

Nieuwlaat R, Wilczynski N, Navarro T, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2014;11:CD000011. PubMed PMC

Viswanathan M, Kahwati LC, Golin CE, Blalock SJ, Coker-Schwimmer E, Posey R, Lohr KN. Medication therapy management interventions in outpatient settings: a systematic review and meta-analysis. JAMA Intern Med. 2015;175:76–87. doi: 10.1001/jamainternmed.2014.5841. PubMed

Koçkaya G, Wertheimer A. Can we reduce the cost of illness with more compliant patients? An estimation of the effect of 100% compliance with hypertension treatment. J Pharm Pract. 2011;24:345–350. doi: 10.1177/0897190010389336. PubMed

IMS Institute of Healthcare Informatics. Avoidable costs in US health care. www.imshealth.com/en_ZA/thought-leadership/ims-institute/reports/avoidable-costs. Accessed February 23, 2017.

Molloy GJ, Messerli-Bürgy N, Hutton G, Wikman A, Perkins-Porras L, Steptoe A. Intentional and unintentional non-adherence to medications following an acute coronary syndrome: a longitudinal study. J Psychosom Res. 2014;76:430–432. doi: 10.1016/j.jpsychores.2014.02.007. PubMed PMC

Pucci M, Martin U. Detecting non-adherence by urine analysis in patients with uncontrolled hypertension: rates, reasons and reactions. J Hum Hypertens. 2017;31:253–257. doi: 10.1038/jhh.2016.69. PubMed

Chatterjee JS. From compliance to concordance in diabetes. J Med Ethics. 2006;32:507–510. doi: 10.1136/jme.2005.012138. PubMed PMC