Although ascertaining whether a patient is truly adherent to antihypertensive medications can be difficult, it is an important first step in the evaluation of the patient with suspected resistant hypertension. Instructing patients to bring all medicines to their appointment provides the opportunity to reconcile medication lists and review how they take their medications. Asking patients in a nonjudgmental way (e.g., “Many patients will occasionally miss a dose—or even a few doses—of their medication(s); how often is missing medications a problem for you?”) about adherence may provide the most accurate answers [11]. Because side effects also may contribute to poor adherence to medications, asking about and addressing them may enhance patients’ understanding and adherence.

It is important to keep the medication regimen as simple as possible. Patients may have difficulty adhering to antihypertensive medications due to financial reasons, or they may not understand the medication regimen due to health literacy and cultural or language barriers. A once-daily regimen improves patients’ adherence to antihypertensive medications [12]. Fixed-dose combination pills, many of which are available as generics, may also improve adherence [13].

Even before ruling out white-coat effect, it is important to rule out measurement error due to poor office BP measurement technique. Confirm that BP has been measured accurately with the patient correctly positioned and not talking following at least a 5-min rest using an appropriately sized cuff [14, 15]. A cuff that is too small will lead to overestimation of BP. Obese patients, who may have large arms, may prove particularly challenging. The use of a thigh cuff or measurement at the forearm, while not ideal, may be necessary [14].

Approximately one-third of patients with apparent resistant hypertension actually have controlled BP when measured outside the office, i.e., “white-coat” effect. In a study of 611 patients with uncontrolled office BP (systolic >140 mmHg or diastolic >90 mmHg), nearly 40 % of those on one or two medications and almost 30 % of those on three medications had controlled BP on ambulatory BP monitoring [16]. In another study of over 8,200 patients with resistant hypertension, 38 % had controlled BP based on a 24-h ambulatory BP monitoring [10]. The white-coat effect may lead to unnecessary increases in dosage or number of antihypertensive medications that could result in hypotension or other side effects.

Automated office devices that take several BPs at preprogrammed intervals without an observer present may be useful to mitigate the white-coat response [17]. Generally, however, given the high prevalence of white-coat effect among patients suspected of having resistant hypertension, out-of-office BP measurements should be used to clarify status (Fig. 42.1). Ambulatory BP monitoring (over 24 h) is the ideal strategy, but is not always available. Home (or self-) BP monitoring is an alternative to ambulatory BP monitoring if the latter is not easily available [18]. Before relying on home BP measurements, it is important to ensure that the patient has the appropriate size cuff and to check the patient’s monitor against a validated clinical device. Patients should be instructed on how to perform home BP measurements and observed to make sure they perform them correctly, and a systematic approach to collecting the measurements like the one shown in Table 42.2 should be used [19]. If home BP monitoring is used and readings suggest white-coat effect, a 24-h ambulatory BP monitoring, if available, should be considered for confirmation. If the 24-h average BP is <130/80 mmHg (or daytime average <135/85 mmHg), the patient can continue current therapy. If the 24-h average BP is ≥130/80 mmHg (or daytime average is ≥135/85 mmHg), BP is confirmed as uncontrolled, and intensification of therapy should be considered.

Certain comorbidities are associated with resistant hypertension. Obesity is common in patients with hypertension and can make hypertension more resistant to treatment due to increased sodium and fluid retention [20]. Therefore, higher doses of antihypertensive medications are often needed. Weight loss must be emphasized not only as an important part of improving overall health but also as an important part of hypertension management. For every kilogram of weight loss, systolic BP is reduced by approximately 1–2 mmHg [21].

Chronic kidney disease (CKD) is also quite common in patients with resistant hypertension [20]. CKD may result from hypertension and, like obesity, makes hypertension more resistant to treatment due to increases in sodium and fluid retention. An emphasis on dietary sodium restriction is therefore particularly warranted in such patients, and a diuretic is almost always required for optimal BP control. Blockade of the renin-angiotensin-aldosterone system with either an ACE inhibitor or ARB (with monitoring of serum potassium levels and glomerular filtration rate) is also part of the hypertension management of the patient with CKD. ACE inhibitors and ARBs should not be used together [22] (Chaps.​ 36 and 41).

Severe atherosclerosis in elderly patients may interfere with accurate BP measurement. When using an upper arm cuff to measure BP, occlusion of the brachial artery should cause disappearance of the ipsilateral radial pulse. If the radial pulse remains palpable despite such occlusion, “pseudohypertension” (falsely elevated BP reading) should be suspected. Clinical clues suggesting pseudohypertension include the development of dizziness or weakness in an elderly patient temporally related to antihypertensive medications and the absence of significant target organ damage despite a very high clinic BP measurement.

While possible secondary causes of hypertension are often considered as part of the initial evaluation of a patient newly diagnosed with hypertension, patients with resistant hypertension comprise a subpopulation in which these causes will be more common. Once hypertension is confirmed as resistant, secondary causes of hypertension should be reconsidered (Table 42.3). Primary aldosteronism, obstructive sleep apnea, and renal artery stenosis are the most common secondary causes to reconsider. Even among patients with resistant hypertension, causes such as hypercortisolism and pheochromocytoma are still rare.

It is important to remember that in addition to antihypertensive medications, the management of hypertension includes lifestyle modifications. A recent study examined healthy lifestyle factors and risk of cardiovascular events in patients with resistant hypertension [41]. Patients who exhibited a greater number of healthy lifestyle factors had a lower risk of cardiovascular events over a mean follow-up of 4.5 years. Thus, for patients with resistant hypertension, lifestyle modifications should be reemphasized. In particular, regular physical activity should be encouraged. Of course, smokers should also be strongly encouraged to quit and offered cessation medications or programs. Patients may not appreciate that the Dietary Approaches to Stop Hypertension (DASH) eating plan combined with low sodium intake can be as effective as a single antihypertensive medication in reducing BP [42]. The importance of weight loss for overweight patients should be emphasized as well.