Resistant hypertension: identification and management

    Hypertension is usually defined as resistant or refractory when a therapeutic plan that includes consideration of lifestyle methods and a prescription of at least three different drugs (including a diuretic) in optimal doses has failed to diminish both systolic and diastolic blood pressure (BP) to threshold. Nevertheless, new data consider those who need four or more drugs to be controlled as resistant hypertensive patients (1). 
    Numerous sources of evidence show that resistant hypertension is a widespread clinical difficulty, although exact incidence is still unknown. Apparently, a patients' prognosis with resistant hypertension is weakened when compared to subjects with more effortlessly managed BP, due to the long and established history of inadequately controlled hypertension and the association with cardiovascular (CV) risk factors. The positive effects of pharmacological treatment are expected as advised in numerous studies. This review focuses on the detection and management of patients with resistant hypertension.

I - Evaluation of patient with resistant hypertension

    Commonly, poor BP control is due to constant systolic BP increases. Advanced age, left ventricular hypertrophy (LVH) and obesity, as well as chronic kidney disease (CKD) or diabetes, all predict treatment resistance. The identification of patients with resistant hypertension should involve 1) verification of true treatment resistance, 2) recognition of sources contributing to treatment resistance - including secondary causes of hypertension, and 3) certification of target-organ damage (Figure) (1). Accurate evaluation of treatment adherence and reliable BP measurement is essential to reject pseudoresistance. 
    A complete clinical history might look for length, severity and development of the hypertension, as well as actual treatment and adherence degree and response to previous pharmacological drugs, including side effects. Symptoms of possible secondary causes of hypertension should be also evaluated, i.e., sleep apnea, renal artery stenosis, and pheochromocytoma (Figure) (1). Use of reliable BP measurement is essential to the precise diagnosis of resistant hypertension. A substantial white-coat effect is expected in patients with resistant hypertension (7), and demands a reliable evaluation of BP measurements with the use of 24-hour ambulatory BP monitoring, particularly in patients whose BP office values are constantly elevated when compared with out-of-office measurements and reveal an absence of target organ damage (1). In addition, higher values of ambulatory BP provide a more exact prediction of future CV disease than office BP values do. A broad physical assessment is needed to reveal secondary causes of hypertension and organ damage. It should include a fundoscopic examination to evaluate the presence and severity of retinopathy, and the exploration of carotid and abdominal bruits and femoral and radial pulses to evaluate both renal artery stenosis and aortic coarctation or aortoiliac disease. Also, a biochemical evaluation should be performed, including a routine metabolic profile, urinalysis and a plasma aldosterone and plasma renin or plasma renin activity to screen for primary aldosteronism (1). A 24-hour urine collection can be helpful in estimating dietary electrolyte intake, creatinine clearance, albumin excretion, metanephrines and measuring aldosterone excretion.

II - Treatment of resistant hypertension

    Appropriate treatment of resistant hypertension is proposed to reverse lifestyle factors contributing to treatment resistance, treat secondary causes of hypertension and include effective use of multi-drug regimens. Lifestyle changes, including weight loss (2), regular exercise (3), ingestion of a high-fiber, low-fat, (4) and low-salt diet (5), treatment of obstructive sleep apnea (6), and moderation of alcohol intake should be encouraged where suitable.  
    Pharmacological treatment should be shortened as much as possible, including the use of a long-acting combination of drugs in order to diminish the number of prescribed pills and to allow for once-daily dosing. Drugs that might hinder with BP control, mainly NSAIDs, should be avoided in subjects with resistant hypertension or, at least, the least efficient dose should be used with prompt down titration and withdrawal as soon as possible, with a close BP monitorisation when using these schedules (1). Treatment resistance has been in part regularly related to a lack of, or underuse of diuretic therapy. In most patients, use of a long-acting thiazide diuretic will be most effective, as they usually have inappropiate volume expansion. In a blinded comparison of hydrochlorothiazide 50 mg and chlorthalidone 25 mg daily, the latter provided greater 24-hour ambulatory BP reduction (9). In patients with underlying CKD, loop diuretics may be necessary for effective volume and BP control. Due to the high incidence of primary aldosteronism in patients with resistant hypertension, mineralocorticoid receptor antagonists have been revealed to provide significant antihypertensive benefit when associated to previous multidrug schedule, even with low doses of spironolactone.
    Although there are few data considering the effectiveness of treatment with fixed combinations of 3 or more drugs, intuitively, it seems suitable to combine drugs with different mechanisms of action, such as an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, calcium channel blocker and a thiazide diuretic. (1,10). Fixed-dose combination therapy can offer potential advantages over individual agents, including enlarged efficiency, diminished incidence of side effects and improved patient compliance through the use of a single pill administered once daily (11,12). 
    Nevertheless, resistant hypertension as a specific subgroup remains understudied. Further added data is needed in order to improve the identification and management of these patients. Effectiveness review of precise multidrug regimens including new therapies is needed. In this way, recent data have been published about the efficacy of a new vasodilatory, selective endothelin type A antagonist, darusentan (12). Renal sympathetic hyperactivity is associated with hypertension and its development, CKD and heart failure. A recent trial shows that a catheter-based renal denervation produces significant and maintained BP decrease in a cohort of resistant hypertensive subjects, without severe adverse events (13).

Figure: Resistant hypertension: diagnostic and treatment recommendations (From Ref. 1)

Conclusion:

Outcome of recent trials have recognised individual features related with resistant hypertension, however underlying mechanisms of treatment resistance, mainly possible genetic mechanisms, have not been extensively examined. Although several pharmacological therapies and lifestyle changes have proved beneficial in subjects with resistant hypertension, additional data is required to improve the identification and treatment of patients with resistant hypertension, and considerations regarding the efficacy of specific multidrug schedules that would help to advance guided therapy.