# Detecting nonadherence to antihypertensive treatment

Idir Hamdidouche, Vincent Jullien, Stéphane Laurent, Michel Azizi

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Idir Hamdidouche, Vincent Jullien, Stéphane Laurent, Michel Azizi. Detecting nonadherence to antihypertensive treatment: Any Time, Anywhere?. Hypertension, 2017, 70 (2), pp.257-258. 10.1161/HYPERTENSIONAHA.117.09739. hal-04052134

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# Detecting Nonadherence to Antihypertensive Treatment
Any Time, Anywhere?

Idir Hamdidouche, Vincent Jullien, Stéphane Laurent, Michel Azizi

**See related article, pp 307–314**

Hypertension remains a leading risk factor for cardiovas-
cular morbidity and mortality.¹ Its management is based
on knowledge accumulated over more than a half a century,
the availability of multiple orally active and potent antihyper-
tensive drugs targeting different pathophysiological pathways,
cumulative evidence from several randomized controlled trials
and meta-analyses, and hundreds of pages of guidelines regu-
larly updated by experts from around the world. Nevertheless,
hypertension remains poorly controlled worldwide, and its
incidence is increasing, because of the aging of the population
and the obesity epidemic.²

Nonadherence to antihypertensive drug treatment and life-
style measures is a key factor underlying poor blood pressure
(BP) control and treatment resistance, and overcoming this
problem is a major public health challenge.³,⁴ Nonadherence
is associated with poor cardiovascular prognosis.⁵ Several
diseases, physician-, treatment- and patient-related factors,
either alone or in combination, promote nonadherence to
treatment and are common to all chronic diseases, including
hypertension.³,⁴

Various direct and indirect methods have been devel-
oped for assessing adherence to drug treatments.³,⁴ The direct
methods include the direct observation of treatment intake
in a medicalized setting, such as a BP clinic, the detection
of a drug or its metabolite in blood or urine, and the deter-
mination of a pharmacodynamic marker.³,⁴ Indirect methods
include patient questionnaires, self-reports, patient diaries,
pill counts, prescription refill rates, the assessment of patient
clinical response, electronic drug monitoring systems, and the
determination of physiological markers.³,⁴

Urinary drug detection has been recently applied to hyper-
tension, in a method based on liquid chromatography coupled
to tandem mass spectrometry (LC-MS/MS) that is highly

sensitive and specific for detecting drugs and determining
their levels in biological samples. The use of this method is
increasing at university hospitals. The presence of the drug,
either in its initial state or as an appropriate metabolite, in
urine demonstrates that the patient has taken the drug within
a time frame dependent on both the dose and the half-life of
the drug.⁶⁻⁸ Technological improvements in LC-MS/MS have
made it possible to identify a large number of molecules by
applying a single procedure to a urine spot sample.

The estimated prevalence of nonadherence to antihy-
pertensive treatment, particularly for patients with resistant
hypertension, has been shown to be higher for LC-MS/MS
than for other methods.⁶⁻⁸ About 50% of the patients attending
specialized BP clinics for resistant hypertension do not com-
ply with the drug regimen prescribed, based on data show-
ing a lack of detection of ≥1 of the antihypertensive drugs
prescribed in plasma or urine.⁶,⁷ There is possibly a bias in
the estimation of the prevalence of nonadherence because of 2
factors acting in opposite directions: the selection of patients
with suspected nonadherence and of patients with suboptimal
BP control in tertiary centers, overestimating the rates of non-
adherence relative to the general hypertensive population, and
the so-called toothbrush adherence phenomenon before each
consultation, with patients taking their medication more reli-
ably just before a consultation, leading to an underestimation
of nonadherence to antihypertensive treatment.

In this issue of the *Hypertension*, McNaughton et al⁹
describe their assessment of adherence to antihypertensive
drugs with an LC-MS/MS blood assay, in 261 adults with
hypertension prescribed at least 1 of the 14 antihypertensive
drugs that can be detected by this assay attending the emer-
gency department of an American university hospital for
reasons other than hypertension or prescription refill. In this
clinical setting, nonadherence was common (28%) despite
patients having a primary care physician and health insur-
ance.⁹ The rate of nonadherence increased with the number of
antihypertensive treatments prescribed: 21.0% of patients pre-
scribed <3 drugs and 41.2% of patients prescribed ≥3 drugs
were classified as nonadherent. Interestingly, for patients
prescribed <3 drugs, BP did not differ between adherent and
nonadherent patients. By contrast, in patients prescribed ≥3
drugs, systolic BP was 20 mm Hg higher in nonadherent than
in adherent patients. Patients prescribed hydrochlorothiazide
were more likely to be nonadherent than patients not pre-
scribed a thiazide.⁹

The emergency department is probably not the ideal loca-
tion to talk to patients about their adherence to treatment, for
many reasons: (1) they may be seeking care for a condition

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

From the Paris-Descartes University, France (V.J., M.A., S.L.); INSERM, CIC1418, Paris, France (I.H., M.A.); Department of Pharmacology (I.H., V.J., S.L.), Hypertension Unit (M.A.), and DHU-PARC (M.A.), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, France; and INSERM UMRS970, Paris, France (V.J., S.L.).

Correspondence to Michel Azizi, Hypertension Unit, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75015 Paris, France. E-mail michel.azizi@aphp.fr

(Hypertension. 2017;70:257-258.

DOI: 10.1161/HYPERTENSIONAHA.117.09739.)

© 2017 American Heart Association, Inc.

Hypertension is available at http://hyper.ahajournals.org

DOI: 10.1161/HYPERTENSIONAHA.117.09739
other than hypertension, (2) BP measurements in this setting do not reflect the ambulatory BP profiles of these patients, (3) information about the precise time at which the drug was last taken is essential for the interpretation of drug detection results but may be difficult for the overworked staff of the emergency department to collect, particularly when patients are seeking attention for another condition. This study acknowledges the limited feasibility of using such an approach in everyday practice, but shows that the detection of nonadherence during a visit to the emergency department provides an additional opportunity to identify and address cases of nonadherence to drug treatment, particularly in patients with uncontrolled BP prescribed >3 drugs, provided that the results of LC-MS/MS assay can be made available to the physician managing the patient within a short time frame.

Nevertheless, LC-MS/MS results may be difficult to interpret without the assistance of pharmacologists and biochemists. Indeed, the nondetection of a drug is not sufficient to conclude with certainty that the patient is not complying with antihypertensive treatment, particularly for short-acting drugs. Between-subject variability and changes in drug pharmacokinetics related to (1) associated comorbid conditions (eg, gastrointestinal bypass, etc.), (2) genetic factors, including polymorphisms of genes encoding drug-metabolizing enzymes or transporters, (3) drug-drug interactions, or (4) interference with food may strongly influence the pharmacokinetics of antihypertensive drugs, resulting in their nondetection in biological samples.⁶,⁷ Conversely, the detection of significant quantities of drugs in plasma or urine is not sufficient to confirm optimal adherence to treatment on a daily basis. Indeed, patients often follow their treatments more reliably during the week before and the week immediately after medical visits.⁴ Finally, the detection of a drug or its metabolite in urine provides only a snapshot of the adherence of a given patient. Adherence is dynamic in nature and may vary between visits.

The suboptimal adherence to drug treatment in hypertension is complex and has multiple causes. Undiagnosed or undeclared nonadherence may lead to (1) various additional (sometimes invasive and often expensive) diagnostic tests in specialized centers to identify the cause of the poor response to antihypertensive medications, (2) inappropriate intensification of antihypertensive treatments, and (3) excessive use of healthcare system resources.⁷ Alternative device-based treatments, including renal denervation, baroreceptor stimulation, and arteriovenous shunting with a coupler, are being developed to achieve the optimal clinical outcome expected from BP reduction in patients with hypertension without having to deal with nonadherence issues.¹⁰ However, patients undergoing renal denervation have a high rate of drug nonadherence, making it difficult to judge a potential benefit of interaction between the effects of the denervation and those of medical therapy.¹¹,¹² These approaches are still experimental and are being tested in

clinical trials. For the moment, efforts to measure and improve adherence to drug treatments may be more cost-effective. However, multiple modes of intervention, including combinations of educational, social, and behavioral strategies, are required to improve adherence to treatment. Their long-term efficacy has yet to be clearly established,¹³ and their implementation in routine clinical practice may be difficult.

## Disclosures

None.

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