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The Evaluation and Treatment of Resistant Hypertension

High blood pressure (HBP) is the phenotypic manifestation of hypertension (HT) and if suboptimally controlled is one of the most attributable risks for cardiovascular (CV) death worldwide.1

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The net adjusted prevalence ratios of HT in the United States continue to increase, but due to increased awareness, there is some improvement in the treatment and control of HT.2 Several large HT outcome trials, however, showed failure to 
achieve BP goals—despite protocol-defined treatment regimens, with 20-35% of the participants not achieving BP control even with more than three antihypertensive medications.3-6

Resistant hypertension (RH) is defined in the 2008 American Heart Association’s scientific statement as BP that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes—one of which is a diuretic—with all drugs prescribed at maximally-tolerated doses.7

Patients who require >4 antihypertensive medications to achieve BP control should also be considered resistant to treatment. This definition does not apply to patients who have recently been diagnosed with HT. RH is a term used to identify patients who are at high risk of having reversible causes of HT, and who may benefit from special diagnostic and therapeutic considerations.7

Prevalence of resistant 

Presently, the true prevalence of RH is not known. A major problem is that not all uncontrolled HT is resistant, based on the definition given by the American Heart Association. Uncontrolled HT that is not resistant is defined as follows: patients who lack BP control secondary to poor adherence and/or inadequate treatment regimen.7

To accurately determine the prevalence of RH, a forced titration study of a large, diverse HT cohort is required. However, several HT studies offer an alternative look at the prevalence of this condition. In a recent National Health and Nutrition Examination Survey (NHANES) survey, only 53% of patients have BP control at <140/90.8 Only thirty-seven percent of participants with chronic kidney disease (CKD), achieve BP control at 130/80 mm Hg.9

In another study using an unselected population sample, the prevalence of RH was 8.9% among individuals, and 12.8% have their BP controlled to <140/90 mm Hg.10 In a cross-sectional analysis of the Framingham Heart Study participants, only 48% had BP control to <140/90, and less than 40% of the elderly participants were at BP goal.11

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial represented the U.S. general population. After roughly five years of follow-up in ALLHAT, 34% of participants remain uncontrolled while on an average of two BP medications. Overall, 51% of participants needed three or more BP medications, indicating resistance.

Prognosis of resistant 

No epidemiological studies have prospectively evaluated the prognosis of patients with RH in comparison to those with Stage 1 HT. Presumably, prognosis will be poor among patients with RH due to long-standing elevated BP and associated CV risks, such as diabetes mellitus, left ventricular hypertrophy (LVH), obstructive sleep apnea (OSA), and/or CKD.12 The Veterans Administration Cooperative Studies demonstrated a 96% reduction in the CV events over 18 months using a triple antihypertensive regimen compared to placebo, suggesting substantial treatment benefit.13

Predictors of resistant 

An analysis of the Framingham study shows that older age was the strongest predictor of poor BP control. Data showed that patients aged >75 years are approximately one fourth as likely as those <60-years-old to have controlled, systolic BP (SBP).14

This may be attributable to the stiffening of the arteries, causing isolated systolic HT in the elderly. Other strong predictors for lack of SBP control are the presence of LVH and obesity. In terms of controlling diastolic BP (DBP), the strongest negative predictor was obesity, as BP was less controlled (by one third) compared to lean patients.15 In the ALLHAT and Framingham studies, older age, higher baseline SBP, LVH, and obesity all predicted treatment resistance.16

One of the strongest predictors of treatment resistance is presence of CKD, stage 3 or higher, defined by serum creatinine >1.5 mg/dl.7 People with diabetes, African Americans (especially women), and those living in the southeastern U.S. are also at increased risk for RH. Both studies indicate that—in an aging population—the prevalence of obesity, CKD, and diabetes increase the risk for RH.