Nonadherence in patients with hypertensive emergency or hypertensive urgency

It is well known that nonadherence to antihypertensive treatment is widespread and may be responsible for apparently treatment‐resistant hypertension, for causing hypertensive crisis, and for avoidable hypertensive end‐organ damage, that is, cardiovascular morbidity and mortality. Specifically, the Frankfurt Hypertension Unit reported in 2013, that in 76 treatment‐resistant hypertensive patients, who did not achieve blood pressure control on a quadruple antihypertensive treatment, 53% were found to be nonadherent by using LC‐MS analysis for antihypertensive drugs or their metabolites in urine.1 About 30% of these nonadherent patients were completely nonadherent and 70% partially nonadherent, thereof 85% with an intake of less than half of drugs prescribed. Using antihypertensive medication refill information in 3550 patients at Kaiser Permanente in Colorado/Northern California with treatment‐resistant hypertension a rate of nonadherence of 42.4% was reported, contraintuitively not being associated with blood pressure control rates while treatment intensification rates were.2 In contrast, a study testing adherence in new referrals, follow‐up patients with inadequate blood pressure control and renal denervation referrals with HP LC‐MS/MS in urine found lower rates of 18.4%, 37.9%, and 23.5% of nonadherence, respectively.3 Overall 10.1% were completely, and 14.9% were partially nonadherent to their antihypertensive treatment. Using a 4‐compartment electronic pillbox in 149 patients with uncontrolled hypertension on 2.6 antihypertensives, a high nonadherence rate [defined as less than 80% adherence] of 42% was found, and both the Morisky Medication Adherence Scale (MMAS‐8) and the Visual Analog Scale (VAS) were only modestly useful in identifying nonadherence.4 However, also electronic monitoring of pill intake has its limitations, especially when compared with direct measurement of antihypertensive drugs in body fluids, since opening the pillbox does not necessarily mean medication intake. On the other hand, an electronic pillbox allows monitoring of adherence over a longer period of time, and direct drug measurements may miss intermittent nonadherence. In the outpatients clinics of a Paris university hospital, a strikingly low rate of 10% nonadherence was reported using UPLC—MS/MS in urine in 174 consecutive, stable hypertensive patients, that were cared for by a single, dedicated physician.5 The MMAS‐4 was not predictive of adherence, when biochemical detection of antihypertensive drugs was used as gold standard. In 238 UK patients referred for LC‐MS/MS screening for antihypertensive drugs, because of some suspicion of suboptimal compliance by their treating doctor, 31% were nonadherent.6 After discussion of nonadherence with all patients, 53% of a subgroup of the UK patients became fully adherent at follow‐up, and in an independent Czech cohort of initially nonadherent patients blood pressure dropped by 32.6/17.4 mm Hg at follow‐up, suggesting that identification of nonadherence and confrontation of patients with nonadherence may improve antihypertensive medication adherence markedly. In the Dutch SYMPATHY trial, where 139 treatment‐resistant hypertensive patients were randomized to renal denervation or control, adherence was assessed at baseline and follow‐up with LC‐MS in blood samples, both patients, and treating physicians being unaware of these measurements.7 When adherence was defined as a 81% or higher match between measured versus prescribed antihypertensive drugs, 80% of patients were nonadherent. In the DENERHTN trial, again antihypertensive medication adherence was assessed in a renal denervation trial by drug screening in urine or plasma.8 In the renal denervation group, 50% of patients were nonadherent at 6 months vs 53% in the control group, respectively.8

In the above‐mentioned studies dealing with antihypertensive medication adherence, high rates of nonadherence of up to 80% have been reported, especially in treatment‐resistant hypertensive patients, in patients evaluated for renal denervation, and to a lesser extent in routine outpatients in a hypertension clinic. Information on nonadherence in patients with hypertensive urgencies or emergencies is scarce, and direct biochemical assessment of adherence in this setting is lacking completely. Therefore, it is of obvious interest for the scientific community to learn more on adherence in this high‐risk patient group.

It is the merit of the study by Wallbach et al9 published in this issue of The Journal of Clinical Hypertensionto report antihypertensive medication adherence by using direct biochemical adherence measurements in hypertensive crisis (hypertensive emergency or hypertensive urgency) for the first time. Patients with hypertensive crisis were in 24% completely and in 34% partially nonadherent with 89% taking less than 50% of their prescribed antihypertensive drugs. Nonadherent patients had a longer hypertension history and were prescribed more antihypertensive, but also general medication. A remarkable additional finding was the high number of blood pressure rising medication and adverse food intake, specifically 33% of patients reported NSAID intake (73% not prescribed, but over‐the‐counter medication), 8% glucocorticoid intake, 10% antidepressants use, as well as 92% caffeine, 20% nicotine, and 10% licorice consumption. This study by Wallbach et al9 thereby adds important novel information on a) a very high rate of nonadherence in patients with hypertensive emergencies or urgencies and b) use of a high percentage of blood pressure increasing medication, especially over‐the‐counter NSAIDs, or consumption of caffeine, nicotin, and licorice in this patient cohort.

Given the high antihypertensive medication nonadherence rate in hypertensive crisis, in treatment‐resistant hypertensive patients, especially patients referred for renal denervation, but also in regular outpatients in general practice and hypertension outpatient clinics, there is a high medical need to improve treatment adherence and thereby outcome of hypertensive patients worldwide. What can we do with regard to solving this problem?

1. Use standard measures to inform/educate the patient about adverse consequences of (untreated) hypertension, available nonmedical (lifestyle changes) and medical treatment, possible side effects and how to handle them, and use pill organizers, pill dispensers, reminders by phone, mail, and text messaging systems.

2. Improve our patient management by using double or triple antihypertensive combination treatment in a single pill as first‐line approach in most hypertensive patients as suggested by the new European Society of Hypertension/European Society of Cardiology (ESH/ERC) guidelines.10 With a simplified approach comprising a step‐wise approach with an initial combination therapy of an ACEi or ARB and a diuretic, consecutive uptitration, and addition of a calcium channel blocker as first steps, the STITCH (Simplified Treatment Intervention To Control Hypertension) study, has resulted in a higher number of patients reaching treatment goals, than with standard Canadian Hypertension Education Program guidelines.11 A large cohort study from Southern California in more than 100 000 hypertensive patients has confirmed, that initial therapy with single‐pill combinations provided better hypertension control in the first year.12

3. Choice of newer classes of drugs such as ARBs, ACEI and calcium channel blockers, lower number of antihypertensive drugs, and less frequent daily administration of antihypertensives affects favorably treatment adherence.13, 14 Use of the smallest effective doses in order to prevent adverse effects of antihypertensive medication should also improve treatment adherence.

4. To increase patient involvement by self‐monitoring of blood pressure has been shown to increase treatment adherence and improve blood pressure control.15

5. Assessing medication adherence by direct biochemical measurement or electronic pillbox and discussing the results with the patient (“adherence counseling”) have been shown to improve adherence to antihypertensive medication and to overcome clinical inertia, that is, a lack of treatment intensification despite uncontrolled hypertension.6, 16 Since subjective estimates of nonadherence by the treating physician are widely inaccurate, and questionnaires overreport adherence, assessing medication adherence by direct biochemical measurement (or electronic pillbox) should become part of daily practice in treating hypertensive patients.17

6. Consider treatment (“out of pocket”) cost for antihypertensive medication, especially, if there is no complete coverage for health care cost by health insurance or by the state. Prescription of inexpensive generic drugs may thus improve adherence.

Given the high rates of nonadherence to antihypertensive medication ranging overall from 10% to 80%, rates of nonadherence for patients with treatment‐resistant hypertension and hypertensive crisis even being in the upper range of 50% to 80%, nonadherence is the single most important issue in order to improve blood pressure control and avoid hypertension‐associated morbidity and mortality. Therefore nonadherence assessment needs to be a routine part of every appointment of a hypertensive patient in private practice or outpatients clinics. Nonadherence assessment should preferentially be done with direct biochemical measurement of the antihypertensive drug concentrations in urine or blood.

CONFLICT OF INTEREST

No conflict of interest.