evaluation of adherence should become an integral part of...

1

• Online Data Supplement

Renal Denervation: An Eye OpenerSince the publication of the first Symplicity studies in 2009 to 2010, renal sympathetic denervation gained acceptance as a novel treatment of drug-resistant hypertension. The latter has been defined as a blood pressure (BP) >140/90 mm Hg, despite appropriate lifestyle measures plus a diuretic and 2 other antihypertensive drugs belonging to different classes at adequate doses.1 According to the US definition, patients with controlled BP on ≥4 antihypertensive drugs are also consid-ered as resistant hypertensives.2 However, a substantial pro-portion of patients with apparently resistant hypertension are in fact poorly adherents to drug treatment. The highly vari-able BP response to renal denervation (RDN)3–5 prompted to a more rigorous evaluation of eligible patients, with the goal to exclude false resistant hypertension, because of poor adherence to drug treatment.6–8 In particular, several publica-tions documented a high proportion of low drug adherence in patients with apparently resistant hypertension (23%–66%), using witnessed drug intake9 or plasma/urine drug determina-tions10–18 (Figure 1).

Furthermore, RDN studies shed the light on the dynamic character of drug adherence. Inclusion in RDN trials may influence drug adherence in various, unpredictable direc-tions.6 In some patients, close follow-up and massive attention devoted to them may lead to improved adherence to lifestyle measures and drug treatment, particularly in the RDN arm (Hawthorne effect). Other patients may stop their medications after RDN according to their perception that the intervention cured their hypertension. On the other hand, patients from the

control group may have not taken their medications properly to keep their BP high, in the hope that this will make them eligible for crossover to the RDN group.

Overall, RDN trials confirm (1) that poor drug adherence is a frequent cause of apparently resistant and difficult- to-treat hypertension, (2) that drug adherence is a dynamic phe-nomenon influenced by complex psychosocial determinants and cannot be captured by any single assessment, (3) and that changes in drug adherence are a major potential confounder in trials assessing new treatment modalities of resistant hypertension.

Although the prevalence of resistant hypertension has been estimated to be 10% to 30%,19,20 it may decrease to <2% when patients with low drug adherence estimated by pharmacy refill are excluded.21 Furthermore, even in those patients with truly resistant hypertension, the benefits of antihypertensive treat-ment are predominantly present in patients with acceptable (>80%) baseline drug adherence, in terms of both BP con-trol and regression of target organ damage.22 Therefore, from a public health and pharmacoeconomic perspective, diagno-sis and management of poor drug adherence in patients with apparently resistant hypertension23 is a priority.

Identification of poorly adherent patients among those with apparently resistant hypertension will avoid unnecessary and potentially harmful treatment intensification and allow implementation of strategies to improve drug adherence.14,24 This approach would be expected to result in a more cost-effective allocation of health resources. Unfortunately, health-care providers underestimate the size of the problem of poor

From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium (A.P., E.B.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (F.R., E.B.); Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium (A.P.); Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (J.A.S.); R&D VitaK Group, Maastricht University, Maastricht, The Netherlands (J.A.S.); Paris-Descartes University, F-75005 Paris, France (M.A.); Assistance Publique-Hôpitaux de Paris, Hypertension Unit, Hôpital Européen Georges Pompidou, F-75015 Paris, France (M.A.); Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigations Cliniques 1418, F-75015 Paris, France (M.A.); Department of Cardiology (S.E.K.) and Department of Nephrology (A.H.), Ullevaal University Hospital, University of Oslo, Oslo, Norway; and Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium (P.W, A.C.).

This article was sent Robert M. Carey, Consulting Editor, for review by expert referees, editorial decision, and final disposition.The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.

116.07464/-/DC1.Correspondence to Alexandre Persu, Cardiology Department, Cliniques Universitaires Saint Luc (UCL), 10 Ave Hippocrate, 1200, Brussels, Belgium.

E-mail [email protected]

Evaluation of Adherence Should Become an Integral Part of Assessment of Patients With Apparently

Treatment-Resistant HypertensionElena Berra, Michel Azizi, Arnaud Capron, Aud Høieggen, Franco Rabbia, Sverre E. Kjeldsen,

Jan A. Staessen, Pierre Wallemacq, Alexandre Persu

(Hypertension. 2016;68:00-00. DOI: 10.1161/HYPERTENSIONAHA.116.07464.)© 2016 American Heart Association, Inc.

Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.116.07464

Brief Review

at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from

mailto:[email protected]

http://hyper.ahajournals.org/







2 Hypertension August 2016

drug adherence. Assessment of adherence is not part of routine clinical practice and is seldom performed in studies, even those testing drugs or interventions in patients with resistant hyper-tension. The finding of persistent tachycardia in a patient on β-blockers suggests a poor adherence or may orient toward a secondary form of hypertension. However, intuitive assessment of adherence by physicians is specific (most patients identified as nonadherent by their physician are indeed so), but lacks sen-sitivity (24%–62% depending on the definition of adherence).25

Moreover, unsubstantiated suspicion of poor adherence in difficult-to-treat patients with resistant hypertension contrib-utes to medical skepticism and therapeutic inertia. Knowing which of their patients do not achieve BP control despite demonstrated good adherence, physicians would feel more motivated and responsible for the optimization of their anti-hypertensive regimen.

The authors of this review article make a plea for a more widespread, systematic, and standardized use of assessment of

drug adherence in patients with apparently resistant hyperten-sion, both in clinical practice and for evaluation of novel drug and interventional strategies, with particular emphasis on drug monitoring its advantages and limitations.

Drug Adherence in Resistant HypertensionDrug adherence is a major concern in hypertensive patients at large, and poor adherence has a demonstrated impact on cardiovascular prognosis (see online-only Data Supplement). Not unexpectedly, poor adherence is particularly frequent in apparently resistant hypertensive patients. Nine recent studies totalizing 747 patients from 5 countries10–18 evaluated the level of adherence in outpatients with resistant or difficult-to-control hypertension using high-performance liquid chromatography coupled with mass spectrometry in urine and plasma. Overall, clinical characteristics, BP values, and average of prescribed drugs per day were similar10–18 (Table 1). The percentage of poor and full nonadherence to drug regimens in these 9 studies

Table 1. Main Characteristics of Patients With Apparently Resistant Hypertension in Whom Drug Adherence Was Tested Using Drug Monitoring

Patients’ CharacteristicsCeral et al

201110

Jung et al 201311

Strauch et al 201312

Tomaszewski et al 201413

Brinker et al 201414

Ewen et al 201515

Patel et al 201516

Hamdidouche et al 201517

Schmieder et al 201618

Resistant hypertensive + + + + + + + + +

Number of patients 84 76 163 66 17 56 100 24 82 79

Mean age, y 55 58 54 57 63 NR 63 65 NR 60

Male, % 60 58 56 42 47 NR 67 62 NR 72

BMI, kg/m2 NR NR 32.3 31.6* 31.9* NR 30.8 33.0 NR 31.1

Number of drugs 5.0±1.2 5 5.2±1.3 NR NR NR 5.2±1.4 3.3±1.7 NR 6.0

Office BP, mm Hg 172/97 NR 175/100 168/95* 168/94* 168/94 167/88 172/92 NR 158/88

24-h ambulatory BP, mm Hg NR NR 156/91 160/91* 160/89* NR 154/86 162/88 NR 155/88

HPLC-MS blood urine blood urine urine blood blood/ urine

urine urine urine

BMI indicates body mass index; BP, blood pressure; HPLC-MS, high-performance liquid chromatography coupled with mass spectrometry; and NR, not reported.*Not available for all patients.

Figure 1. Proportion of poor or nonadherence according to drug monitoring in different cohorts of patients with apparently resistant hypertension. Black indicates total nonadherence, whereas gray indicates partial adherence. Partial adherence was defined as the presence of at least one undetectable drug10–12,14,16–18 or as the presence of fewer medications than prescribed.13,15

at KU Leuven University Library on June 16, 2016http://hyper.ahajournals.org/Downloaded from


Berra et al Drug Monitoring in Patients With Resistant Hypertension 3

ranged from 13% to 46% and from 2% to 35%, respectively (Figure 1).

However, it should be kept in mind that these measurements give only a snapshot of evaluation of adherence. In view of the known phenomenon of white coat adherence or toothbrush effect (increased adherence during the few days preceding a medical contact),26 daily-life drug adherence between 2 visits may be overestimated. Unfortunately, most of these studies have important limitations: (1) no rigorous definition of resis-tant hypertension or of partial adherence was provided10,13,14; (2) details on the antihypertensive regimen were not reported13,14; (3) patients included were not always on optimal antihyper-tensive therapy and did not always meet strict criteria of drug resistance10,13,14; (4) details on methodology of drug dosage were not reported14,16; (5) the timing of the samplings after the last drug intake was not cleary defined13–16,18; (6) the possible influence of preanalytical errors and pharmacokinetics on the level of drugs detected was not discussed10,11,13,16,18; (7) it was not clearly explained whether patients gave informed consent to have their adherence assessed and when10,11,14; (8) and pre-dictors of poor adherence were not analyzed.10,14–16,18

Methods to Evaluate Drug AdherenceOver time, adherence has been studied using increasingly reli-able and sophisticated methods. According to the method used, assessment of drug adherence can take place at different steps of the patient’s pathway (physician’s office, pharmacy, home; Figure 2). These different approaches to assess drug adher-ence can be divided into 2 categories: indirect and direct meth-ods. Indirect methods include assessment by the clinician,25 self-assessment by the patient (interviews/questionnaires),27,28 measurement of pharmacodynamics parameters (heart rate for β-blockers, lack of rise of plasma renin for renin–angioten-sin inhibitors, which may be also due to undetected primary aldosteronism-,29 as well as acetyl-SDKP measurements for

angiotensin-converting enzyme inhibitors,),30 pill counts,31 and prescription refill. Direct methods include witnessed drug intake, Medication Event Monitoring System (MEMS), tele-monitoring, and drug monitoring in body fluids.

The choice to use a method rather than another depends on multiple factors, including reliability, sensitivity to white-coat adherence, educational value, local facilities, long-term feasibility, patient profile, and financial resources (Table 2). All methods have limitations, and ideally, accurate evalu-ation of adherence should involve a combination of several approaches.

Bobrie et al evaluated adherence in a cohort of 164 resistant hypertensive patients on a standardized triple anti-hypertensive therapy, which were randomized to 2 different treatment strategies (sequential nephron blockade versus renin–angiotensin system blockade).32 Subsequently, the same group evaluated the influence of adherence on the efficacy of these 2 approaches.22 The authors used 2 indirect and 2 direct methods to assess adherence, assigning one point to each drug adherence measurement to calculate a global score.22 The superiority of sequential nephron blockade over renin–angio-tensin system blockade in terms of BP control and regression of target organ damage (arterial stiffness and left ventricular mass) was significant only in adherent patients. Along simi-lar lines, in a cohort of >240 000 newly treated hypertensive patients from the Italian Lombardy region, followed for 6 years, patients with a drug coverage ≥75% (24% of the cohort) had a 25% lower risk of cardiovascular events compared with those with a coverage <25% (22% of the cohort).33

Indirect methods are simple, inexpensive, and time-effi-cient, and they imply a reasonable workload.27,34–36 On the other hand, the sensitivity of these methods is poor35,37–40; they are heavily dependent on patient behavior,41,42 affected by social desirability and recall biases,43–47 and fail to provide information about the timing of doses, which is an essential

Figure 2. Patient pathway from drug prescription at the physician’s office to next control visit, highlighting the different possible levels of drug adherence monitoring.




aspect of adherence.48 Accordingly, they are poorly corre-lated with direct methods such as MEMS and drug dosage in body fluids.35,37,42,44,45,47 In particular, in a sample of 47 patients with apparently resistant hypertension, poor adher-ence was grossly underestimated by the Morisky Medication Adherence Scale-8 (26%) compared with drug monitoring (51%).47 Compared with the latter, the sensitivity of Morisky Medication Adherence Scale-8 was found to be 26%, speci-ficity 75%, positive predictive value 50%, and negative pre-dictive value 51%.

Direct methods are more accurate and reliable49 than indirect methods, but also more expensive and demanding in terms of human resources.44,50

Witnessed drug intake combined with ambulatory BP measurement might appear as a gold standard but cannot give information about persistence. Its application requires a hos-pital environment and the involvement of dedicated, trained healthcare professionals. The strength of this method is to provide an immediate proof that the prescribed medication in the prescribed doses is effective, if taken. On the other hand, witnessed drug intake raises ethical issues. Its use is justified in highly contagious and potentially fatal diseases such as tuberculosis, but less in hypertension, which only in the long-term leads to cardiovascular complications.51 Therefore, this approach is appropriate only within the framework of clinical studies.9,52

Telemonitoring allows obtaining a higher number of BP measures and improves the patient–physician communica-tion. Furthermore, it improves patient compliance and hence BP control.53–55 Moreover, nowadays, the use of memory-equipped BP monitors allows overcoming problems related to the reliability of reports by patients.56 However, telemonitor-ing involves a high workload for the healthcare professionals, which limits its applicability in clinical practice.57,58

The MEMS system provides detailed information about the timing of drug intake and missing doses.40,59 It can be used long term, favors patient empowerment, and

has a demonstrated educational value.60,61 Accordingly, it has been associated with improved drug adherence.57,58,60–62 Nevertheless, electronic monitoring has an important limita-tion: it does not allow detecting patients who willingly open the box without swallowing the pill. Such behavior may be over-represented in the subgroup of difficult-to-treat patients referred for RDN.63,64 This intrinsic disadvantage can be overcome by the use of an ingestible sensor65,66 but the latter is expensive, is invasive, has not been validated on a large scale, and is not free from possible side effects, such as skin allergies caused by the patch and possible gut retention of its metal components.

The alternative is measuring drug/metabolite levels in body fluids. In hypertensive patients, the most widely used matrices for drug measurements are blood and urine.10–18 High-performance liquid chromatography coupled with a sensitive detector such as mass spectrometry is considered the reference analytic technique.67 Although widely used for drug monitoring, blood has the disadvantage to require inva-sive sampling and relatively accurate blood drawing time, especially for drugs with higher clearance. Even though urine provides a larger detection window as compared with blood, none of these matrices are able to assess if the treatment is rig-orously followed between medical visits. Possible alternative approaches and matrices for drug monitoring are discussed in the online-only Data Supplement.

Drug monitoring is objective in detecting in a semiquanti-tative manner the presence or not of drugs in body fluids, but cannot give precise quantitative information, such as whether the patient is at his/her maximal tolerated dose.45,59 In contrast to electronic drug monitoring, it allows to test adherence for all drugs, which is not a trivial asset in view of the known differ-ences in adherence according to drug class.68–70 Nevertheless, drug monitoring provides no information on the timing of drug intake or on the persistence on treatment. Furthermore, in con-trast with MEMS,60,61 the educational value of repeated drug monitoring has not been studied in depth. Still, in a cohort

Table 2. Advantages and Disadvantages of Different Methods to Assess Drug Adherence

Advantages and Disadvantages

Indirect Methods Direct Methods

Assessment by Clinician Questionnaires Pill Count

Prescription Refill

Witnessed Drug Intake

Electronic Monitoring Tele-Monitoring

Drugs Dosage in Body Fluids

Advantages Objectivity ↓↓↓↓ ↓↓↓ ↓↓ ↓↓↓ ↑↑↑↑ ↑↑ ↑↑ ↑↑↑

Accuracy ↓↓↓↓ ↓↓↓ ↓↓ ↓↓↓ ↑↑↑↑ ↑↑↑ ↑↑ ↑↑↑

Feasibility ↑↑↑↑ ↑↑↑↑ ↑↑↑ ↑ ↓↓↓ ↑ ↓↓ ↓

Educational value

↓↓↓ ↑↑ ↑ – ↑ ↑↑↑↑ ↑↑↑ ↑↑

Disadvantages Cost/workload ↓↓↓↓ ↓↓↓ ↓↓↓ ↑ ↑↑ ↑↑↑ ↑↑↑↑ ↑↑

White coat effect

– – ↑↑↑ – – ↓↓↓ ↑↑ ↑↑↑

Social desirability

bias

↓↓↓↓ ↑↑↑↑ ↑↑↑ ↑↑ – ↑↑ ↑↑↑ ↓↓

Manipulability ↓↓↓↓ ↑↑ ↑↑↑↑ ↑↑↑ ↓↓↓↓ ↑↑↑↑ ↓↓ ↓↓↓

Social desirability bias: people respond to questioning in ways that make them seem more appealing to others or to healthcare providers. Manipulability: patients willingly manipulate the results of the assessment.




of 56 patients with apparently resistant hypertension, Brinker et al documented a sustained BP decrease (−46±10/−26±14 mm Hg; P<0.01) after information about the undetectable level of prescribed drugs, focused discussion and counseling, in the absence of drug treatment adjustment.14

Drug monitoring is sensitive to white-coat adherence, especially if the patient has been informed in advance.46 Nevertheless, this disadvantage can be partly overcome if drug monitoring is performed at short notice (ie, the day the patient provides his informed consent) or chronically at irregular intervals (the patient knows that adherence will be regularly checked but does not know when). Finally, to avoid misclassification of patients as adherent or nonadher-ent, the interpretation of drug monitoring results requires a good knowledge of the influence of pharmacokinetics, phar-macogenetics, and pharmacological interactions on the level of drugs in body fluids. This may be particularly relevant in patients with resistant hypertension who are often obese, on complex drug regimens, or have altered renal function.20 These aspects, as well as the advantages and disadvantages of different body fluids for drug measurement, will be discussed in the following sections.

Influence of Pharmacokinetics and Preanalytical Errors on Drug Monitoring

The clinician should be aware that blood concentration of drugs may be influenced by factors other than treatment adherence (Figure 3). In particular, pharmacokinetics may be highly variable for some drugs, resulting in high or on the con-trary low or even undetectable blood or urine levels, depend-ing on the sensitivity of the analytical method. The most frequent causes of variability in drug concentration include comedication with enzymatic inducers or inhibitors, diarrhea,

malabsorption, obesity,71,72 food interference, salt intake,73 edema, ascites, as well as hepatic and renal impairment.

Polymorphism of genes involved in drug metabolism or distribution is another important source of variability in phar-macokinetics (fast metabolizers, increased efflux transport pro-tein expression, etc). For example, torasemide is metabolized by CYP2C9, which has been described to be polymorphic, with ethnicity being involved.74 The majority of β-blockers (metoprolol, nebivolol, timolol, and to a lesser extent, propran-olol, carvedilol, and bisoprolol) are metabolized by CYP2D6. Notably, the variable number of functional copies of the CYP2D6 gene (from 0 to 13) may have a substantial influence on the plasma concentration of the corresponding drugs.75 The frequency of fast or even ultrarapid metabolizers again may vary according to the ethnicity (1%–29%), leading to lower through concentrations.76–78 Some angiotensin type I receptors blockers (losartan, irbesartan, candesartan) are metabolized by the polymorphic CYP2C9.79 Finally, calcium antagonists are mainly substrates for highly polymorphic CYP3A4 3A5 enzymes.80–82 Table 3 summarizes the pharmacokinetic char-acteristics of the most frequently used antihypertensive drugs belonging to the 5 main classes.83–93

Drug monitoring may also be influenced by preanalytical errors. False-negative results might be because of nonspe-cific drug adsorption on the plastic tube or separator gel used or to drug instability at higher temperature or sensitivity to light as described for nifedipine.94 Moreover, P-glycoprotein and CYP3A4 inhibitors such as itraconazole markedly raise plasma concentrations of aliskiren and enhance its renin-inhibiting effect. The interaction is probably mainly explained by inhibition of the P-glycoprotein-mediated efflux of aliski-ren in the small intestine, with a minor contribution from inhi-bition of CYP3A4.95

Figure 3. Flow chart summarizing the different causes of low drug levels in plasma/urine to be considered before labeling a patient as poorly adherent.




Psychology and EthicsEvaluation of adherence raises several ethical issues. First, before suspecting a problem of poor adherence, physicians should make sure that the diagnosis is correctly established and therapy is of known efficacy and appropriate for the patient’s attitudes and cultural beliefs.96 The importance of drug adher-ence should be discussed with patients, and unless there is an imminent necessity, assessment of adherence should not be

performed without informing patients. Appropriate discussion of results of drug monitoring with the patient may improve patient–physician relationship, favor patient’s empower-ment, and lead to improved drug adherence and subsequent BP control.14 Nevertheless, labeling a patient as poorly or nonadherent should be made with caution because adher-ence is a dynamic phenomenon (a patient may be adherent today, not tomorrow), and low drug dosages obtained by drug

Table 3. Pharmacokinetic Characteristics of the 5 Major Classes of Antihypertensive Drugs

Drugs Bioavaibility, % T1/2, h Vd, L/kgCLp,

mL/min/kgProtein

Binding, % MetabolismMain Route of

Elimination References

Diuretics

Hydrochlorothiazide60–80 2.5 0.83 NA 60 Not known

Renal (≥65% unchanged)

Laurence et al83

Indapamide100 14–16 21 NA 80

Hepatic (CYP3A4,hydrolase)

Renal [70%] (≤7% unchanged)

Chaffman et al84

Spironolactone60–90 1.3 NA NA ≥90 Hepatic

Renal [25%–55%] (mainly as

metabolites)

Laurence et al83

Chlorthalidone

54–74 25–69 0.14 0.04 75

Renal [60%–70%]

(mainly unchanged)

Laurence et al83

Beta blockers

Lipophilic (carvedilol, labetalol, metoprolol)

10–80 3–7 1.5–4 10–2550–98

(10 for met.)

Hepatic (CYP1A2, 2D6, 3A4, 2C9,

2E1), some active metabolites

Renal [60%–90%] (<10% unchanged)

Laurence et al83, McNeil

and Louis85

Hydrophilic (atenolol)30–50 4–24 0.5–2 1–3 <5–30

Minimal hepatic metabolism

Renal [30%–80%] (almost entirely

unchanged)

Laurence et al83

Intermediate (bisoprolol) 50–90 2–22 1–5 5–10 30–50

Hepatic (CYP2D6, 3A4)

Renal [20%–70%] (20%–50% unchanged)

Johns et al88, Kendall89

Calcium antagonists

Amlodipine60–65 30–50 12–20 4–8 ≥90

Hepatic (probably CYP3A4)

Renal [70%] (<10% unchanged)

Laurence et al83

Diltiazem30–50 3–7 3.3 12–21 80 Hepatic (CYP3A4-5)

Renal [50%] (2%–4%

unchanged)

Laurence et al83

ACE inhibitors

Captopril65–75 1–2 0.7 13 30 Hepatic

Renal [80%] (40%–50% unchanged)

Romankiewicz et al91

Lisinopril25–50 12 1–3 1–3 31 None

Renal [35%] (totally unchanged)

Laurence et al83

ARB

Olmesartan26 9–18 0.36 0.31 99

Gastrointestinal tract

Renal (35%–50% unchanged)

Laurence et al83

Irbesartan60–80 11–15

59–960.87 90

Hydrolysis Hepatic (CYP2C9)

Renal [50%] (<2% unchanged)

Ruilope 92

Candesartan15–40 4–9 0.13 0.37 >99

Minor hepatic metabolism

Renal (20%–30% unchanged)

Gleiter et al93

ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blockers; CLp, plasmatic clearance; met, metoprolol; NA, not available; NS, not significant;

T1/2

, half-life; and Vd, volume of distribution.




monitoring may reflect technical artifacts or pharmacokinetic effects (Figure 3). Another important aspect is the way of communication between patient and physician: stigmatiza-tion of poorly adherent patients should be avoided and physi-cians should be empathic rather than inquisitive. Physicians must not forget that attempts to improve patient’s adherence by threatening are unethical, and there are no evidences of their effectiveness in the literature. Instead, there are other means of demonstrated efficacy to improve adherence with long-term treatments: simplifying the regimens and counsel-ing about it using educational materials, such as reminders for medications and appointments, implementing medical visits, and involving family members.96

Cost-Effectiveness of Drug MonitoringThe high prevalence of poor adherence in patients with appar-ently resistant hypertension raises the issue of cost-effective-ness of drug monitoring. In the German Healthcare System, the cost for the high-performance liquid chromatography coupled with mass spectrometry is ≈60€ per test.11 This may seem a lot, but it is necessary to compare this investment with the global cost of managing resistant hypertensive patients. This includes ruling out secondary hypertension, costs of addi-tional antihypertensive drugs, and in some cases, the cost of new device-based therapies, such as RDN or baroreflex activa-tion therapies. The cost for the screening of a secondary form of arterial hypertension is >250€,11 and the yield is expected to be low. Furthermore, it is estimated that additional drugs, 1 or 2 pills per patient, for a period of only 6 to 12 weeks cost as much as liquid chromatography–mass spectrometry.97

More recently, using a Markov model to evaluate the incremental cost-effectiveness ratio, Chung et al demonstrated that optimal management of resistant hypertension, includ-ing drug monitoring, is cost-effective in a wide age range (30–90 years) compared with optimal management without drug monitoring.23 Notably, although the model assumed an overall 20 mm Hg drug monitoring–related reduction in sys-tolic BP over the patients’ lifetime, drug monitoring remains cost-effective if systolic BP remains at the initial level in 50% of patients. Even more so, the use of drug monitoring to con-trol for adherence before considering invasive procedures, such as renal sympathetic denervation or baroreflex activa-tion therapy, is likely to be highly cost-effective. Indeed, the direct interventional cost for renal sympathetic denervation is already at 4000€98 and a baroreflex activation therapy costs as much as 20 000€.99 Hypothesizing a population of 100 patients with apparently resistant hypertension and assuming that all patients will undergo RDN or baroreflex activation therapy, the cost will be 400 000€ for RDN and 2 000 000€ for baroreflex activation therapy. If detection of nonadherence by drug monitoring allows decreasing by 50% the number of patients eligible for RDN or baroreflex stimulation, the global saving will be of 1 200 000€.11

ConclusionsThe authors make a plea for a better study and wider use of direct methods to evaluate drug adherence in patients with difficult-to-treat and apparently resistant hypertension.

The main priorities for the next 5 years are the following:

• Better information of healthcare professionals, patients, and the lay public on the importance of a good drug adherence.

• Generalization of the use of validated adherence ques-tionnaires (such as Morisky questionnaire)28 in patients with hypertension.

• Routine use of direct evaluation of drug adherence before considering complex or costly diagnostic procedures,100 further treatment intensification, or the use of invasive, expensive nondrug treatments (RDN, baroreflex stimula-tion) in patients on 4 drugs or more.

• Identification of the most adequate target population, for which direct methods of assessment of adherence are cost-effective and should be implemented.

• Determination of the best method or combination of methods to assess adherence in the long term in this tar-get group. Drug monitoring is a good candidate, espe-cially for the initial evaluation of adherence, if possible associated with other methods such as MEMS, for long-term follow-up and improvement of adherence.

• Standardization of the definition of partial and total adherence.

• Standardization of the methods of drug monitoring and assessment of the contribution of pharmacokinetic factors versus poor adherence on low drugs dosage in body fluids.

• Establishment of registries of adherence in the specific population of patients with apparently resistant hyper-tension, allowing further identification of predictors of poor adherence and, conversely, the barriers to a good adherence.

• Identification of distinct profiles of poor or nonadherent patients (careless, absent-minded, or badly organized patients, nonbelievers in the efficacy of drugs or having adverse events versus psychiatric patients who willingly do not take drugs).

• Study of the most efficient approaches to improve long-term drug adherence in these different types of patients.24

AcknowledgmentsWe are grateful to Mrs Hélène Langet for her technical assistance and to Mr Robert Jung for his help with Figure 2.

DisclosuresNone.

References 1. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guide-

lines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–2219. doi: 10.1093/eurheartj/eht151.

2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252. doi: 10.1161/01.HYP.0000107251.49515.c2.

3. Persu A, Jin Y, Azizi M, et al; European Network COordinating research on Renal Denervation (ENCOReD). Blood pressure changes after renal denervation at 10 European expert centers. J Hum Hypertens. 2014;28:150–156. doi: 10.1038/jhh.2013.88.




4. Persu A, Azizi M, Jin Y, Volz S, Rosa J, Fadl Elmula FE, Pechere-Bertschi A, Burnier M, Mark PB, Elvan A, Renkin J, Sapoval M, Kahan T, Kjeldsen S, Staessen JA; European Network COordinating research on Renal Denervation (ENCOReD) consortium. Hyperresponders vs. nonresponder patients after renal denervation: do they differ? J Hypertens. 2014;32:2422–2427; discussion 2427. doi: 10.1097/HJH.0000000000000347.

5. Azizi M, Sapoval M, Gosse P, et al; Renal Denervation for Hypertension (DENERHTN) investigators. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resis-tant hypertension (DENERHTN): a multicentre, open-label, ran-domised controlled trial. Lancet. 2015;385:1957–1965. doi: 10.1016/S0140-6736(14)61942-5.

6. Persu A, Kjeldsen S, Staessen JA, Azizi M. Renal denervation for treat-ment of hypertension: a second start and new challenges. Curr Hypertens Rep. 2016;18:6. doi: 10.1007/s11906-015-0610-9.

7. Mahfoud F, Böhm M, Azizi M, et al. Proceedings from the European clini-cal consensus conference for renal denervation: considerations on future clinical trial design. Eur Heart J. 2015;36:2219–2227.

8. White WB, Galis ZS, Henegar J, Kandzari DE, Victor R, Sica D, Townsend RR, Turner JR, Virmani R, Mauri L. Renal denervation therapy for hypertension: pathways for moving development forward. J Am Soc Hypertens. 2015;9:341–350. doi: 10.1016/j.jash.2015.02.012.

9. Fadl Elmula FE, Hoffmann P, Fossum E, Brekke M, Gjønnæss E, Hjørnholm U, Kjær VN, Rostrup M, Kjeldsen SE, Os I, Stenehjem AE, Høieggen A. Renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before quali-fying ambulatory blood pressure. Hypertension. 2013;62:526–532. doi: 10.1161/HYPERTENSIONAHA.113.01452.

10. 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-responsive-ness from non-adherence to recommended therapy. Hypertens Res. 2011;34:87–90. doi: 10.1038/hr.2010.183.

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

12. 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.

13. 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.

14. 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.

15. 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.

16. Patel P, Gupta PKC, White CMJ, 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. 2015. doi:10.1038/jhh.2015.103. [Epub ahead of print].

17. Hamdidouche I, Jullien V, Billaud EM, Boutouyrie P, Azizi M, Laurent S. 7B.06: routine urinary detection of antihypertensive drugs for esti-mation of adherence to treatment: a cross sectional study. J Hypertens. 2015;33(suppl 1):e93. doi: 10.1097/01.hjh.0000467603.33785.69.

18. 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;12:1–10.

19. De la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, Oliveras A, Ruilope LM. Clinical features of 8295 patients with resis-tant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57:898–902.

20. Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011;57:1076–1080. doi: 10.1161/HYPERTENSIONAHA.111.170308.

21. Weitzman D, Chodick G, Shalev V, Grossman C, Grossman E. Prevalence and factors associated with resistant hypertension in a large health main-tenance organization in Israel. Hypertension. 2014;64:501–507. doi: 10.1161/HYPERTENSIONAHA.114.03718.

22. Beaussier H, Boutouyrie P, Bobrie G, Frank M, Laurent S, Coudoré F, Azizi M. True antihypertensive efficacy of sequential nephron blockade in patients with resistant hypertension and confirmed medication adherence. J Hypertens. 2015;33:2526–2533. doi: 10.1097/HJH.0000000000000737.

23. Chung O, Vongpatanasin W, Bonaventura K, Lotan Y, Sohns C, Haverkamp W, Dorenkamp M. Potential cost-effectiveness of therapeutic drug moni-toring in patients with resistant hypertension. J Hypertens. 2014;32:2411–2421; discussion 2421. doi: 10.1097/HJH.0000000000000346.

24. Parthan A, Vincze G, Morisky DE, Khan ZM. Strategies to improve adherence with medications in chronic, ‘silent’ diseases representing high cardiovascular risk. Expert Rev Pharmacoecon Outcomes Res. 2006;6:325–336. doi: 10.1586/14737167.6.3.325.

25. Miller LG, Liu H, Hays RD, Golin CE, Beck CK, Asch SM, Ma Y, Kaplan AH, Wenger NS. How well do clinicians estimate patients’ adherence to combination antiretroviral therapy? J Gen Intern Med. 2002;17:1–11.

26. Burnier M, Wuerzner G, Struijker-Boudier H, Urquhart J. Measuring, analyz-ing, and managing drug adherence in resistant hypertension. Hypertension. 2013;62:218–225. doi: 10.1161/HYPERTENSIONAHA.113.00687.

27. Haynes RB, Taylor DW, Sackett DL, Gibson ES, Bernholz CD, Mukherjee J. Can simple clinical measurements detect patient noncompliance? Hypertension. 1980;2:757–764.

28. Morisky DE, Green LW, Levine DM. Concurrent and predictive valid-ity of a self-reported measure of medication adherence. Med Care. 1986;24:67–74.

29. Rossi GP. A comprehensive review of the clinical aspects of primary aldosteronism. Nat Rev Endocrinol. 2011;7:485–495. doi: 10.1038/nrendo.2011.76.

30. Azizi M, Ménard J, Peyrard S, Lièvre M, Marre M, Chatellier G. Assessment of patients’ and physicians’ compliance to an ACE inhibi-tor treatment based on urinary N-acetyl Ser-Asp-Lys-Pro determination in the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study. Diabetes Care. 2006;29:1331–1336. doi: 10.2337/dc06-0255.

31. Pearson RM. Who is taking their tablets? Br Med J (Clin Res Ed).1982;285:757–758.

32. Bobrie G, Frank M, Azizi M, Peyrard S, Boutouyrie P, Chatellier G, Laurent S, Menard J, Plouin PF. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. J Hypertens. 2012;30:1656–1664. doi: 10.1097/HJH.0b013e3283551e98.

33. Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, Mancia G. Better compliance to antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011;29:610–618. doi: 10.1097/HJH.0b013e328342ca97.

34. Alcoba M, Cuevas MJ, Perez-Simon MR, Mostaza JL, Ortega L, Ortiz de Urbina J, Carro JA, Raya C, Abad M, Martin V; HAART Adherence Working Group for the Province of Leon, Spain. Assessment of adher-ence to triple antiretroviral treatment including indinavir: role of the determination of plasma levels of indinavir. J Acquir Immune Defic Syndr. 2003;33:253–258.

35. Zeller A, Ramseier E, Teagtmeyer A, Battegay E. Patients’ self-reported adherence to cardiovascular medication using electronic monitors as com-parators. Hypertens Res. 2008;31:2037–2043. doi: 10.1291/hypres.31.2037.

36. He W, Bonner A, Anderson D. Patient reported adherence to hypertension treatment: A revalidation study. Eur J Cardiovasc Nurs. 2015;19:1–7.

37. Gilbert JR, Evans CE, Haynes RB, Tugwell P. Predicting compliance with a regimen of digoxin therapy in family practice. Can Med Assoc J. 1980;123:119–122.

38. Kass MA, Gordon M, Meltzer DW. Can ophthalmologists correctly identify patients defaulting from pilocarpine therapy? Am J Ophthalmol. 1986;101:524–530.

39. Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed? A novel assessment technique. JAMA. 1989;261:3273–3277.

40. Cate H, Bhattacharya D, Clark A, Holland R, Broadway DC. A com-parison of measures used to describe adherence to glaucoma medica-tion in a randomised controlled trial. Clin Trials. 2015;12:608–617. doi: 10.1177/1740774515592636.

41. Rudd P, Byyny RL, Zachary V, LoVerde ME, Mitchell WD, Titus C, Marshall G. Pill count measures of compliance in a drug trial: variability and suitability. Am J Hypertens. 1988;1(3 pt 1):309–312.




42. Pullar T, Kumar S, Tindall H, Feely M. Time to stop counting the tablets? Clin Pharmacol Ther. 1989;46:163–168.

43. Murri R, Ammassari A, Trotta MP, et al; AdICoNa Study Group. Patient-reported and physician-estimated adherence to HAART: social and clinic center-related factors are associated with discordance. J Gen Intern Med. 2004;19:1104–1110. doi: 10.1111/j.1525-1497.2004.30248.x.

44. Bruxvoort K, Festo C, Cairns M, Kalolella A, Mayaya F, Kachur SP, Schellenberg D, Goodman C. Measuring patient adherence to malaria treatment: a comparison of results from self-report and a customised elec-tronic monitoring device. PLoS One. 2015;10:e0134275. doi: 10.1371/journal.pone.0134275.

45. McRae-Clark AL, Baker NL, Sonne SC, DeVane CL, Wagner A, Norton J. Concordance of Direct and Indirect Measures of Medication Adherence in A Treatment Trial for Cannabis Dependence. J Subst Abuse Treat. 2015;57:70–74. doi: 10.1016/j.jsat.2015.05.002.

46. Fabbiani M, Di Giambenedetto S, Cingolani A, Fanti I, Colafigli M, Tamburrini E, Cauda R, Navarra P, De Luca A, Murri R. Relationship between self-reported adherence, antiretroviral drug concentration mea-surement and self-reported symptoms in patients treated for HIV-1 infection. Infect Dis (Lond). 2016;48:48–55. doi: 10.3109/23744235.2015.1082034.

47. 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.

48. Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: methods, validity, and applications. J Clin Epidemiol. 1997;50:105–116.

49. Jasmer RM, Seaman CB, Gonzalez LC, Kawamura LM, Osmond DH, Daley CL. Tuberculosis treatment outcomes: directly observed therapy compared with self-administered therapy. Am J Respir Crit Care Med. 2004;170:561–566. doi: 10.1164/rccm.200401-095OC.

50. Frieden TR, Sbarbaro JA. Promoting adherence to treatment for tuber-culosis: the importance of direct observation. Bull World Health Organ. 2007;85:407–409.

51. Eskås PA, Heimark S, Eek Mariampillai J, Larstorp AC, Fadl Elmula FE, Høieggen A. Adherence to medication and drug monitoring in apparent treatment-resistant hypertension. Blood Press. 2016; 5:1–7.

52. Kjeldsen SE, Os I. Cost-effectiveness of therapeutic drug monitor-ing in patients with resistant hypertension and improving patients’ adherence. J Hypertens. 2014;32:2357–2358. doi: 10.1097/HJH. 0000000000000385.

53. Pickering TG, Gerin W, Holland JK. Home blood pressure teletrans-mission for better diagnosis and treatment. Curr Hypertens Rep. 1999;1:489–494.

54. Rogers MA, Small D, Buchan DA, Butch CA, Stewart CM, Krenzer BE, Husovsky HL. Home monitoring service improves mean arterial pressure in patients with essential hypertension. A randomized, controlled trial. Ann Intern Med. 2001;134:1024–1032.

55. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ; Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Recommendations for blood pressure measure-ment in humans and experimental animals: Part 1: blood pressure mea-surement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142–161. doi: 10.1161/01.HYP.0000150859.47929.8e.

56. Mengden T, Hernandez Medina RM, Beltran B, Alvarez E, Kraft K, Vetter H. Reliability of reporting self-measured blood pressure values by hyper-tensive patients. Am J Hypertens. 1998;11:1413–1417.

57. Bedra M, Finkelstein J. Introducing home blood pressure telemoni-toring for children with hypertension. Stud Health Technol Inform. 2015;216:889.

58. Spruill TM, Williams O, Teresi JA, et al. Comparative effectiveness of home blood pressure telemonitoring (HBPTM) plus nurse case manage-ment versus HBPTM alone among Black and Hispanic stroke survivors: study protocol for a randomized controlled trial. Trials. 2015;16:97. doi: 10.1186/s13063-015-0605-5.

59. Morrison A, Stauffer ME, Kaufman AS. Defining medication adherence in individual patients. Patient Prefer Adherence. 2015;9:893–897. doi: 10.2147/PPA.S86249.

60. Burnier M, Schneider MP, Chioléro A, Stubi CL, Brunner HR. Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions. J Hypertens. 2001;19:335–341.

61. Burnier M, Santschi V, Favrat B, Brunner HR. Monitoring compliance in resistant hypertension: an important step in patient management. J Hypertens Suppl. 2003;21:S37–S42.

62. Christensen A, Osterberg LG, Hansen EH. Electronic monitoring of patient adherence to oral antihypertensive medical treatment: a systematic review. J Hypertens. 2009;27:1540–1551. doi: 10.1097/HJH.0b013e32832d50ef.

63. Handler J. Malingering: an unusual cause of resistant hyper-tension. J Clin Hypertens (Greenwich). 2012;14:475–478. doi: 10.1111/j.1751-7176.2012.00633.x.

64. Pessina AC, Bisogni V, Fassina A, Rossi GP. Munchausen syndrome: a novel cause of drug-resistant hypertension. J Hypertens. 2013;31:1473–1476. doi: 10.1097/HJH.0b013e328360e9ae.

65. Belknap R, Weis S, Brookens A, Au-Yeung KY, Moon G, DiCarlo L, Reves R. Feasibility of an ingestible sensor-based system for monitor-ing adherence to tuberculosis therapy. PLoS One. 2013;8:e53373. doi: 10.1371/journal.pone.0053373.

66. Chai PR, Castillo-Mancilla J, Buffkin E, Darling C, Rosen RK, Horvath KJ, Boudreaux ED, Robbins GK, Hibberd PL, Boyer EW. Utilizing an ingestible biosensor to assess real-time medication adherence. J Med Toxicol. 2015;11:439–444.

67. Maurer HH. Current role of liquid chromatography-mass spectrometry in clinical and forensic toxicology. Anal Bioanal Chem. 2007;388:1315–1325. doi: 10.1007/s00216-007-1248-5.

68. Morgan SG, Yan L. Persistence with hypertension treatment among com-munity-dwelling BC seniors. Can J Clin Pharmacol. 2004;11:e267–e273.

69. Veronesi M, Cicero AF, Prandin MG, Dormi A, Cosentino E, Strocchi E, Borghi C. A prospective evaluation of persistence on antihypertensive treatment with different antihypertensive drugs in clinical practice. Vasc Health Risk Manag. 2007;3:999–1005.

70. Simons LA, Ortiz M, Calcino G. Persistence with antihyperten-sive medication: Australia-wide experience, 2004-2006. Med J Aust. 2008;188:224–227.

71. McLeay SC, Morrish GA, Kirkpatrick CM, Green B. The relationship between drug clearance and body size: systematic review and meta-anal-ysis of the literature published from 2000 to 2007. Clin Pharmacokinet. 2012;51:319–330. doi: 10.2165/11598930-000000000-00000.

72. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the phar-macokinetics of drugs in humans. Clin Pharmacokinet. 2010;49:71–87. doi: 10.2165/11318100-000000000-00000.

73. Azizi M, Blanchard A, Charbit B, Wuerzner G, Peyrard S, Ezan E, Funck-Brentano C, Ménard J. Effect of contrasted sodium diets on the pharmacokinetics and pharmacodynamic effects of renin-angiotensin system blockers. Hypertension. 2013;61:1239–1245. doi: 10.1161/HYPERTENSIONAHA.113.01196.

74. Matthaei J, Brockmöller J, Tzvetkov MV, Sehrt D, Sachse-Seeboth C, Hjelmborg JB, Möller S, Halekoh U, Hofmann U, Schwab M, Kerb R. Heritability of metoprolol and torsemide pharmacokinetics. Clin Pharmacol Ther. 2015;98:611–621. doi: 10.1002/cpt.258.

75. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003;348:529–537. doi: 10.1056/NEJMra020021.

76. Blake CM, Kharasch ED, Schwab M, Nagele P. A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics. Clin Pharmacol Ther. 2013; 3:394–399.

77. Lefebvre J, Poirier L, Poirier P, Turgeon J, Lacourciere Y. The influence of CYP2D6 phenotype on the clinical response of nebivolol in patients with essential hypertension. Br J Clin Pharmacol. 2007;63:575–582. doi: 10.1111/j.1365-2125.2006.02796.x.

78. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clini-cal significance: Part I. Clin Pharmacokinet. 2009;48:689–723. doi: 10.2165/11318030-000000000-00000.

79. Cabaleiro T, Román M, Ochoa D, Talegón M, Prieto-Pérez R, Wojnicz A, López-Rodríguez R, Novalbos J, Abad-Santos F. Evaluation of the relationship between sex, polymorphisms in CYP2C8 and CYP2C9, and pharmacokinetics of angiotensin receptor blockers. Drug Metab Dispos. 2013;41:224–229. doi: 10.1124/dmd.112.046292.

80. Wang XF, Yan L, Cao HM, Wei LM, Yang WH, Zhang SJ, Zhang LR. Effect of CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1 C3435T on the pharmacokinetics of nifedipine in healthy Chinese vol-unteers. Int J Clin Pharmacol Ther. 2015;53:737–745. doi: 10.5414/CP202211.

81. Zhou YT, Yu LS, Zeng S, Huang YW, Xu HM, Zhou Q. Pharmacokinetic drug-drug interactions between 1,4-dihydropyridine calcium channel blockers and statins: factors determining interaction strength and relevant clinical risk management. Ther Clin Risk Manag. 2014;10:17–26. doi: 10.2147/TCRM.S55512.




82. Zhang YP, Zuo XC, Huang ZJ, Cai JJ, Wen J, Duan DD, Yuan H. CYP3A5 polymorphism, amlodipine and hypertension. J Hum Hypertens. 2014;28:145–149. doi: 10.1038/jhh.2013.67.

83. Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e. New York: McGraw-Hill. 2011.

84. Chaffman M, Heel RC, Brogden RN, Speight TM, Avery GS. Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension. Drugs. 1984;28:189–235.

85. McNeil JJ, Louis WJ. Clinical pharmacokinetics of labetalol. Clin Pharmacokinet. 1984;9:157–167. doi: 10.2165/00003088-198409020- 00003.

86. Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS. Nadolol: a review of its pharmacological properties and therapeutic efficacy in hyper-tension and angina pectoris. Drugs. 1980;20:1–23.

87. Milne RJ, Buckley MM. Celiprolol. An updated review of its pharma-codynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs. 1991;41:941–969.

88. Johns TE, Lopez LM. Bisoprolol: is this just another beta-blocker for hypertension or angina? Ann Pharmacother. 1995;29:403–414.

89. Kendall MJ. Clinical relevance of pharmacokinetic differences between beta blockers. Am J Cardiol. 1997;80(9B):15J–19J.

90. Malhotra HS, Plosker GL. Barnidipine. Drugs. 2001;61:989–996; discus-sion 997.

91. Romankiewicz JA, Brogden RN, Heel RC, Speight TM, Avery GS. Captopril: an update review of its pharmacological properties and thera-peutic efficacy in congestive heart failure. Drugs. 1983;25:6–40.

92. Ruilope L. Human pharmacokinetic/pharmacodynamic profile of irbesar-tan: a new potent angiotensin II receptor antagonist. J Hypertens Suppl. 1997;15:S15–S20.

93. Gleiter CH, Jägle C, Gresser U, Mörike K. Candesartan. Cardiovasc Drug Rev. 2004;22:263–284.

94. Shamsipur M, Hemmateenejad B, Akhond M, Javidnia K, Miri R. A study of the photo-degradation kinetics of nifedipine by multivariate curve resolution analysis. J Pharm Biomed Anal. 2003;31:1013–1019.

95. Tapaninen T, Backman JT, Kurkinen KJ, Neuvonen PJ, Niemi M. Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. J Clin Pharmacol. 2011;51:359–367. doi: 10.1177/0091270010365885.

96. Haynes RB, McDonald HP, Garg AX. Helping patients follow prescribed treatment: clinical applications. JAMA. 2002;288:2880–2883.

97. Kassenärztliche Bundesvereinigung. Beschluss des Gemeinsamen Bundesausschusses über die Änderung der Arzneimittel-Richtlinie (AM-RL) in Anlage IV: Therapiehinweis zu Aliskiren vom 17. Dezember 2009 [German National Association of Statutory Health Insurance Physicians. Decision of the Joint Federal Board (G-BA) on modifications to the pharmaceutical guidelines (AM-RL) in attach-ment IV: Therapy advice on Aliskiren, 17 December 2009]. Dtsch Arztebl. 2010; 107:A1035–A1037.

98. Geisler BP, Egan BM, Cohen JT, Garner AM, Akehurst RL, Esler MD, Pietzsch JB. Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol. 2012;60:1271–1277. doi: 10.1016/j.jacc.2012.07.029.

99. Young KC, Teeters JC, Benesch CG, Bisognano JD, Illig KA. Cost-effectiveness of treating resistant hypertension with an implantable carotid body stimulator. J Clin Hypertens (Greenwich). 2009;11:555–563. doi: 10.1111/j.1751-7176.2009.00163.x.

100. Ruzicka M, Hiremath S. Can drugs work in patients who do not take them? The problem of non-adherence in resistant hypertension. Curr Hypertens Rep. 2015;17:579. doi: 10.1007/s11906-015-0579-4.



Jan A. Staessen, Pierre Wallemacq and Alexandre PersuElena Berra, Michel Azizi, Arnaud Capron, Aud Høieggen, Franco Rabbia, Sverre E. Kjeldsen,

Apparently Treatment-Resistant HypertensionEvaluation of Adherence Should Become an Integral Part of Assessment of Patients With

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 2016 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension published online June 13, 2016;Hypertension.

http://hyper.ahajournals.org/content/early/2016/06/13/HYPERTENSIONAHA.116.07464.citationWorld Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://hyper.ahajournals.org/content/suppl/2016/06/13/HYPERTENSIONAHA.116.07464.DC1.htmlData Supplement (unedited) at:

http://hyper.ahajournals.org//subscriptions/

is online at: Hypertension Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertensionin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:


http://hyper.ahajournals.org/content/early/2016/06/13/HYPERTENSIONAHA.116.07464.citation

http://hyper.ahajournals.org/content/suppl/2016/06/13/HYPERTENSIONAHA.116.07464.DC1.html

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://hyper.ahajournals.org//subscriptions/


1

Online Supplement

EVALUATION OF ADHERENCE SHOULD BECOME AN INTEGRAL

PART OF ASSESSMENT OF PATIENTS WITH APPARENTLY

TREATMENT-RESISTANT HYPERTENSION

Short title: drug monitoring in patients with resistant hypertension

Elena Berra, Michel Azizi, Arnaud Capron, Aud Høieggen, Franco Rabbia,

Sverre E. Kjeldsen, Jan A. Staessen, Pierre Wallemacq, Alexandre Persu.

Conflict of interest: NONE

Word Counts: Text 6.554, including references

Word Counts for abstract: 249

Number: Figures 3; Table: 3

Correspondence:

Alexandre Persu, M.D.-Ph.D.

Cardiology Department

Cliniques Universitaires Saint Luc (UCL)

10 Avenue Hippocrate

1200, Brussels

Belgium

Phone +32-2-764 63 06

Fax: +32-2-764 28 36

E-mail: [email protected]

mailto:[email protected]

2

Drug adherence in the general hypertensive population

Adherence is a complex and dynamic phenomenon. It is defined as the intake of the correct drug at

the correct dose at the correct time1,2. Furthermore, drug adherence also includes persistence, which

is the continuous use of medications for the specified treatment time period3,4. Two types of non-

adherence have been identified: intentional non-adherence and non-intentional non-adherence5.

Self-reported reasons for intentional non-adherence include: absence of symptoms, the belief that

stress reduction may allow controlling blood pressure without drugs, fear of addiction, tolerance or

side effects and preference for alternative medicine. In contrast, non-intentional poor adherence

may be due to forgetfulness, problems of organization, cost of drugs and medical visits and

difficulties in accessing health insurance5.

Adherence is a major health problem in chronic diseases. This is particularly true for a usually

asymptomatic disease -or risk factor- such as hypertension 3. In a population of 18.806 newly

diagnosed hypertensive patients, followed by 400 Italian primary care physicians, the proportion of

days covered by therapy during a mean of six months of follow- up was ≤40% in 51% of patients 6.

Similar results have been found in 82.824 newly-treated hypertensive elderly patients, of which

only 51% were persistent with therapy for one full year 7. Even using self-reporting questionnaires,

which are likely to overestimate adherence 8, the rate of adherence still remains at 53% 9. Along the

same lines, in a longitudinal database including 4783 hypertensive patients using electronic

monitoring for 30 to 330 days, as much as 10% of the prescribed doses were omitted every day 10.

In particular, 42% of patients forgot to take their therapy for one day only, 15% for one or two days

and 43% for three or more days. In 13% of patients, “drug holidays” of two months or more were

observed 10.

Predictive factors of a poor drug adherence in the general hypertensive population include young

age, sex 9,11,12 , comorbidities, pill burden, high number of daily intakes, number and nature of drugs 9,13-15, the presence of side effects 13,16, socio-cultural level, health service access and poor patient-

physician interaction 17. Other predictors of adherence include: depression, cognitive impairment,

inadequate follow-up, cost of medication, patient’s lack of belief in benefit of treatment and

patient’s poor insight into the illness 3.

Impact of poor adherence on cardiovascular risk

Evidence is growing that patients with a poor level of adherence are at increased risk of

cardiovascular events compared to adherent patients. In a cohort study of 18.806 newly diagnosed

hypertensive patients, Mazzaglia et al. observed a significantly increased risk of acute

cardiovascular events in patients with low level of adherence (≤ 40%) compared with highly

adherent patients (≥80%) (hazard ratio: 1.61; p = 0.032) 6. Similarly, in a retrospective analysis,

hypertensive patients with low (< 60%) and moderate (60%-79%) adherence were more likely to be

hospitalized for a cardiovascular event (odds ratio 1.33 and 1.28, respectively; p < 0.001) than

adherent patients (≥ 80%) 18. Along the same lines, in a population-based retrospective study

including 31.306 newly treated hypertensive patients, the risk of all-cause death, stroke, or acute

myocardial infarction was higher in patients with poor adherence (≤ 40%) compared to patients

with good (61% to 80%) or excellent adherence levels (> 80%) (hazard ratio: 1.45 and 1.89

respectively, p = 0.001) 19. Finally, Kim et al. evaluated the effect of antihypertensive medication

adherence on incidence of ischemic heart disease, cerebral haemorrhage, and cerebral infarction in a

population of about 34.000 hypertensive subjects for a period of five years. Drug adherence was

assessed using a cumulative medication adherence scale based on pharmacy claims data. Patients

with poor medication adherence (< 50%) had a higher mortality from ischemic heart disease

(hazard ratio, 1.64; p= 0.005), cerebral haemorrhage (hazard ratio, 2.19; p =0.004), and cerebral

infarction (hazard ratio, 1.92; p = 0.003) compared to those with good adherence (≥ 80%) 20.

3

Alternative approaches for drug monitoring

The emerging technology of dried blood spot (DBS) sampling offers new possibilities. DBS

capillary blood is obtained from a finger prick with a lancet by the patient himself. The DBS

sampling technique is minimally invasive and therefore ideal for routine clinical testing. Sample

storage and shipment is easy with a reduced biological hazard. After drying, the paper with the

blood spot sample is mailed to the analytical laboratory. The laboratory punches out a disk from the

blood spot before extraction of target drug(s). The size of the paper disk provides a volumetric

measurement similar to liquid measurement devices. The advantages of DBS-based methods

coupled with improved analytical instrumental capability have led to an increasing interest in this

methodology for various applications including drug monitoring, toxicology and pharmacokinetic

studies. This emerging technology has been used for bisoprolol and ramipril 21-25, but, to our

knowledge, has not been validated for other antihypertensive drugs. The risk to have false negatives

is higher with DBS than with blood or urine samples. This is because of the small amount of

blood/urine compared to a blood or urine sample. Future implementation of DBS needs further

investigations and will require highly sensitive assays. Finally, in the future, the DBS-sampling

technique could be replaced by point-of-care-testing (POCT). POCT has the advantage to avoid

shipping of samples and to allow evaluation of adherence and discussion of the results with the

patient at the same consultation. Nowadays, POCT has been already successfully used for detection

of drugs of abuse in urine or saliva 22,23 and determination of plasma levels of glycated

haemoglobin, total cholesterol, triglycerides and albumin-creatinine ratio 24 . In addition to blood

and urines, the use of alternative matrices such as saliva 30 and hair 29 may be considered in the

future. Saliva has been used for monitoring patient compliance with psychiatric medications, anti-

epileptic drugs, some anti-cancer drugs and antiretroviral agonists in HIV carriers patients 26-28.

Collection of saliva does not require needle, lancet or technical expertise and is totally non-invasive,

resulting generally in a better acceptance. A preliminary assessment and validation of the relation

between drug concentrations in saliva/hair and blood is of course mandatory. Another aspect to take

into consideration is the fact that, in contrast to blood, in the saliva most of the drugs will be present

as unbound fraction. The presence of a drug in the saliva will be influenced by its physico-chemical

properties, its interaction with the cells and tissues of the salivary glands as well as by extravascular

drug metabolism. Therefore, this approach may not be appropriate for all drugs. Finally, as the

concentration of drugs in hair reflects uptake from the systemic circulation over an extended time

window (weeks to months), hair analysis may provide advantages over plasma or saliva monitoring

in assessing average drug exposure over a longer period of time. This approach has been recently

explored in anticancer and anti-HIV medications 29. Furthermore, unlike phlebotomy, hair

collection is not invasive and does not require particular skills, refrigeration, or sterile equipment.

4

References:

1. Lüscher TF, Vetter W. Adherence to medication. J Hum Hypertens 1990;4:43-46.

2. Ho PM, Bryson CL, Rumsfeld JS. Medication Adherence: Its Importance in Cardiovascular

Outcomes. Circulation 2009;119:3028-3035.

3. Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med. 2005;353:487-497.

4. Burnier M. Medication adherence and persistence as the cornerstone of effective antihypertensive

therapy. Am J Hypertens. 2006;19:1190-1196.

5. Marshall IJ, Wolfe CD, McKevitt C. Lay perspectives on hypertension and drug adherence:

systematic review of qualitative research. BMJ. 2012;345:1-16.

6. Mazzaglia G, Ambrosioni E, Alacqua M, Filippi A, Sessa E, Immordino V, Borghi C, Brignoli

O, Caputi AP, Cricelli C, Mantovani LG. Adherence to antihypertensive medications and

cardiovascular morbidity among newly diagnosed hypertensive patients. Circulation

2009;120:1598-1605.

7. Morgan SG, Yan L. Persistence with hypertension treatment among community-dwelling BC

seniors. Can J Clin Pharmacol. 2004; 11:267-273.

8. Zeller A, Taegtmeyer A, Martina B, Battegay E, Tschudi P. Physicians' ability to predict patients'

adherence to antihypertensive medication in primary care. Hypertens Res. 2008; 31:1765-1771.

9. Ramli A, Ahmad NS, Paraidathathu T. Medication adherence among hypertensive patients of

primary health clinics in Malaysia. Patient Prefer Adherence. 2012;6:613-622.

10. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed

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

BMJ 2008; 336:1114–1117.

11. Monane M, Bohn RL, Gurwitz JH, Glynn RJ, Levin R, Avorn J. The effects of initial drug

choice and comorbidity on antihypertensive therapy compliance: results from a population-based

study in the elderly. Am J Hypertens. 1997;10:697-704.

12. Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, Mancia G. Better compliance

to antihypertensive medications reduces cardiovascular risk. J Hypertens 2011; 29:610-618.

13. Veronesi M, Cicero AF, Prandin MG, Dormi A, Cosentino E, Strocchi E, Borghi C. A

prospective evaluation of persistence on antihypertensive treatment with different antihypertensive

drugs inclinical practice. Vasc Health Risk Manag. 2007; 3:999-1005.

14. Simons LA, Ortiz M, Calcino G. Persistence with antihypertensive medication: Australia-wide

experience, 2004-2006. MJA 2008;188:224-227.

15. Van Wijk BL, Klungel OH, Heerdink ER, de Boer A. Rate and determinants of 10-year

persistence with antihypertensive drugs. J Hypertens 2005;23:2101-2107.

16. Tedla YG, Bautista LE. Drug Side Effect Symptoms and Adherence to Antihypertensive

Medication. Am J Hypertens. 2015;185:1-8.

5

17. Hedna K, Hakkarainen KM, Gyllensten H, Jönsson AK, Andersson Sundell K, Petzold M, Hägg

S. Adherence to Antihypertensive Therapy and Elevated Blood Pressure: Should we Consider the

Use of Multiple Medications? PLoS One. 2015;11:1-14.

18. Pittman DG, Tao Z, Chen W, Stettin GD. Antihypertensive medication adherence and

subsequent healthcare utilization and costs. Am J Manag Care. 2010;16:568-576.

19. Degli Esposti L, Saragoni S, Benemei S, Batacchi P, Geppetti P, Di Bari M, Marchionni N,

Sturani A, Buda S, Degli Esposti E. Adherence to antihypertensive medications and health

outcomes among newly treated hypertensive patients. Clinicoecon Outcomes Res. 2011; 3:47-54.

20. Kim S, Shin DW, Yun JM, Hwang Y, Park SK, Ko YJ, Cho B. Medication Adherence and the

Risk of Cardiovascular Mortality and Hospitalization Among Patients With Newly Prescribed

Antihypertensive Medications. Hypertension. 2016 ;67:506-512.

21. Lawson G, Cocks E, Tanna S. Bisoprolol, ramipril and simvastatin determination in dried blood

spot samples using LC-HRMS for assessing medication adherence. J Pharm Biomed Anal. 2013;

81-82:99-107.

22. Barrett C, Good C, Moore C. Comparison of point-of-collection screening of drugs of abuse in

oral fluid with a laboratory-based urine screen. Forensic Sci Int. 2001; 122:163-166.

23. Mastrovitch TA, Bithoney WG, DeBari VA, Nina AG. Point-of-care testing for drugs of abuse

in an urban emergency department. Ann Clin Lab Sci. 2002 ;32:383-386.

24. Bubner TK, Laurence CO, Gialamas A, Yelland LN, Ryan P, Willson KJ, Tideman P, Worley

P, Beilby JJ. Effectiveness of point-of-care testing for therapeutic control of chronic conditions:

results from the PoCT in General Practice Trial. Med J Aust. 2009;190:624-626.

25. McElnay JC. DBS sampling: a journey. Bioanalysis 2015; 16:1967-1970.

26. Dwivedi R, Gupta YK, Singh M, Joshi R, Tiwari P, Kaleekal T, Tripathi M. Correlation of

saliva and serum free valproic acid concentrations in persons with epilepsy. Seizure. 2015; 25:187-

190.

27. Estrela RC, Ribeiro FS, Seixas BV, Suarez-Kurtz G. Determination of lopinavir and ritonavir in

blood plasma, seminal plasma, saliva and plasma ultra-filtrate by liquid chromatography/tandem

mass spectrometry detection. Rapid Commun Mass Spectrom. 2008; 22:657-664.

28. Gras A, Schneider S, Karasi JC, Ternes AM, Sauvageot N, Karasi-Omes C, Henry AP, Schmit

JC, Seguin-Devaux C, Arendt V. Evaluation of saliva as an alternative matrix for monitoring

plasma Zidovudine, Lamivudine and nevirapine concentrations in Rwanda. Curr HIV Res. 2011;

9:223-228.

29. Olds PK, Kiwanuka JP, Nansera D, Huang Y, Bacchetti P, Jin C, Gandhi M, Haberer JE.

Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair

among children in rural Uganda. AIDS Care. 2015;27:327-332.

30. Pappadopulos E, Jensen PS, Chait AR, Arnold LE, Swanson JM, Greenhill LL, Hechtman L,

Chuang S, Wells KC, Pelham W, Cooper T, Elliott G, Newcorn JH. Medication adherence in the

MTA: saliva methylphenidate samples versus parent report and mediating effect of concomitant

behavioral treatment. J Am Acad Child Adolesc Psychiatry 2009; 5:501-510.

evaluation of adherence should become an integral part of...

Documents