It is becoming increasingly apparent that uncontrolled resistant hypertension, especially in the primary care setting, is most often attributable to pseudocauses of treatment resistance, including inaccurate blood pressure (BP) measurement, white-coat effect, under treatment, and poor medication adherence. Of these, the latter two are likely the most common. In the current issue of the Journal, Durand et al. provide insight into this important clinical issue by quantifying the range and overall degree of poor medication adherence among patients with resistant hypertension based on a rigorous systematic review and meta-analysis of studies that had reported adherence in patients with resistant hypertension.
Inaccurate BP measurement, especially when done by auscultation, is known to be commonly inaccurate in routine clinical settings. Such inaccuracies have been shown recently to result in the common misdiagnosis of uncontrolled resistant hypertension. Bhatt et al. compared the routine triage BP measurements with measurements done in the same patients by trained clinicians with use of an automated, oscillometric device in 130 patients referred to a university hypertension specialty clinic for uncontrolled resistant hypertension. The triage BP measurements were done by patient technicians using an automated device to obtain a single BP reading. These measurements were done in a busy patient intake area, immediately after having the patient sit down, and often during ongoing questioning of the patient's interval medical history. The BP measurement done by trained clinicians was done within 5 min of the triage BP, after having the patient sit in a quiet, private room for 3–5 min, and was the average of the final five of six serial readings taken 1-min apart with use of a properly sized cuff. The serial readings were done unattended, that is, without any clinical staff present.
The investigators found that the triage or routinely done measurements tended to overestimate the levels obtained with use of rigorous BP technique, such that 33% of the patients would have been falsely diagnosed as having uncontrolled resistant hypertension based solely on the triage BP assessments. Among the patients identified as having falsely high BP, the median triage BP level was 155/95 versus 129/75 mmHg in the same patients when measured by trained clinicians with standardized technique. These findings highlight that BP readings done in a routine clinical setting are often inaccurate, most often falsely high, and as a consequence represent an important cause of pseudoresistance.
A prominent white coat is likewise a common cause of pseudoresistance in patients with uncontrolled resistant hypertension. Analyzing treated hypertensive patients from the Spanish Ambulatory Blood Pressure Monitoring Registry, de la Sierra et al. identified more than 8000 patients with resistant hypertension based on elevated office BP levels, despite being treated with three or more antihypertensive agents, including a diuretic. Of these, almost 38% had white-coat resistant hypertension, that is, elevated office BP levels, but controlled 24-h BP levels during ambulatory monitoring.
Although the above findings clearly demonstrate that a large white-coat effect is a common cause of pseudoresistance, affecting more than one-third of patients with seemingly uncontrolled resistant hypertension, it is important to recognize that such patients tend to progress to development of true sustained resistant hypertension, such that continued, close monitoring of out-of-office BP readings is indicated. Muxfeldt et al. did serial 24-h ambulatory BP assessments in 198 patients with confirmed white-coat resistant hypertension. By 18 months, approximately 50% of the patients had progressed to having elevated ambulatory BP levels, consistent with true, sustained resistant hypertension. Combined, the findings of de la Sierra et al. and Muxfeldt et al. demonstrate that a prominent white-coat effect is also a common cause of pseudotreatment resistance, but that such patients are also at high risk at progressing in a short period of time to true, sustained resistant hypertension.
Undertreatment and poor adherence likely represent the two most common causes of pseudoresistance to antihypertensive treatment. In terms of the former, large observational studies suggest that as many as one-half of patients with apparent resistant hypertension are not receiving optimal treatment because of prescription of multiple-drug regimens at submaximal dose amounts and lack of use of a diuretic. For example, Egan et al. evaluated the electronic medical record data from over 200 community-based primary care clinics. This analysis included over 465 000 patients being treated for hypertension, of whom, about one-third were uncontrolled. Almost 45 000 patients met the criteria for having resistant hypertension based on being treated with three or more medications, but only about one-half of these patients were being well treated, based on treatment regimens that included a diuretic and all agents having been prescribed at least 50% of the maximum recommended dose amount.
Per recommendations of the American Heart Association Scientific Statement on the Evaluation and Treatment of Resistant Hypertension published in 2008, treatment regiments for resistant hypertension should include use of a long-acting thiazide-like diuretic, such as chlorthalidone, and a mineralocorticoid receptor antagonist (MRA), such as spironolactone . However, such agents are infrequently used, especially by primary care clinicians. For example, of the 78 participants in a large community-based cohort who were prescribed five or more antihypertensive agents because of persistent, uncontrolled hypertension, chlorthalidone was one of those agents less than 5% of the time, and an MRA less than 20% of the time .
Multiple studies have indicated that poor adherence, or even total lack of adherence, is common in patients with resistant hypertension. To a certain extent, this is intuitive, as it is well known that adherence declines as the number of medications increases and as the complexity of the dosing regimen increases. These studies, however, have been limited in reporting a very wide range in adequate adherence with a low of less than 10% and a high of greater than 80%. This wide range is, in no doubt, related to broad differences in study methodologies, particularly in how adherence was indexed. Studies have estimated adherence based on clinician impression, patient self-report, pill counts, electronic pill monitoring, directly observed pill administration, prescription refill rates, and direct measurement of drug and/or drug metabolites in blood or urine.
Durand et al. provide some coherence to these widely divergent findings in providing a systematic evaluation of all published studies of sufficient scientific rigor to provide an overall estimate of medication adherence among patients with resistant hypertension. The meta-analysis combined results from 24 studies that had utilized the different methods of indexing patient adherence. The pooled participant sample included over 68 000 patients with resistant hypertension, although more than 60 000 of the patients were from a single study that had utilized prescription refill rates to quantify adherence. Utilizing the rates of nonadherence as reported by each study, the authors report that the pooled prevalence of nonadherence of all the studies was 31%. The nonadherence rate ranged from a high of 86% based direct measurement of serum drug levels to a low of 3% based on pill counts.
The meta-analysis of Durand et al. provides important insight in estimating that one-third of patients with resistant hypertension remain uncontrolled because of poor adherence to pharmacologic treatment. It is important to recognize, however, that this is a pooled estimate based on a spectrum of methodologies to index adherence ranging from patient self-report to direct measurement of serum or urinary drug levels. The former tends to indicate much higher levels of adherence than the latter. Intuitively, one would tend to think that objectively determining the presence or absence of medication would be more accurate than subjective recall by the patient, but assays of drug levels are not readily available to most clinicians, whereas query of medication adherence should be a routine part of the patient visit. Accordingly, the current study results highlight the clinical reality that poor adherence is a common cause of pseudoresistance to antihypertensive treatment, but findings highlight that methods to identify nonadherence vary widely in terms of practicality, such that clinicians will have to remain versatile in applying those methods on an individual patient basis.
Overall, the findings of Durand et al. and prior studies add to a growing body of literature demonstrating that resistant hypertension often does not represent true treatment failure, but is instead attributable to common pseudocauses of treatment resistance. Accordingly, effective management of resistant hypertension firstly requires reliable confirmation of true treatment resistance based on accurate BP measurement, exclusion of a prominent white-coat effect, determination of adequate medication adherence, and then, optimization of treatment.
The study was funded by the National Institutes of Health (NIH R01 HL113004) and the American Heart Association (SFRN 15SFRN2390002) (D.A.C.).
Conflicts of interest
ReCor Medical (D.A.C.).
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