ABSTRACT: New insights on resistant hypertension and new guidelines for diagnosis and management can help physicians address this increasingly common and distinct condition.
CME OBJECTIVE: The reader will better understand how to evaluate and treat people with resistant hypertension and when to refer patients to a specialist.
David A. Calhoun, MD, no conflicts of interest
The American Heart Association (AHA) released its first consensus statement in April 2008 to address resistant hypertension—blood pressure that remains above target goals in individuals using three antihypertensive medications of different classes (Hypertension. 2008;51:1403-1419). The AHA recognized the need for strategies specifically dedicated to diagnosis and management of resistant hypertension, which is increasing in prevalence, says UAB hypertension specialist David A. Calhoun, MD, who chaired the guideline writing committee. "Older age and obesity are two of the strongest risk factors associated with resistant hypertension, and physicians can anticipate the condition becoming an increasingly common problem among their patients."
The guideline's definition of resistant hypertension is generally consistent with earlier characterizations, but the report adds an important distinction, Calhoun says. "Previously experts believed that blood pressure had to remain uncontrolled to be considered resistant, but we now recognize that people who need four or more medications to control blood pressure are clinically different from those who achieve control with one or two drugs," he says. "People needing four or more drugs to reach target goals may benefit from the diagnostic and therapeutic considerations reviewed in these guidelines."
A secondary impetus for the guidelines, Calhoun says, was highlighting the underlying causes of resistant hypertension as an understudied but high-priority area for future research.
Prevalence, Risk Factors
Clinical trial data suggest that up to 30% of people being treated for high blood pressure are not reaching levels <140/90 mm Hg. Increasing rates of diabetes mellitus and chronic kidney disease (CKD) are likely to drive prevalence of resistant hypertension even higher.
People with CKD and diabetes, for whom the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommended lower targets of <130/80 mm Hg, have higher rates of resistant hypertension.
In an analysis of Framingham Heart Study data the most robust indicator of poor blood pressure control was age. "Vessels stiffen and lose vascular compliance as we age, resulting in high blood pressure that is more difficult to treat," Calhoun says. "Why vascular stiffening occurs with aging is unknown—it does not seem to be an inevitable consequence of growing older, and is probably linked to Westernized diets and lifestyles."
In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), older age, obesity, left ventricular hypertrophy, and higher baseline systolic blood pressure all predicted therapeutic resistance (J Clin Hypertens. 2002;4:393-404). In this study, the presence of CKD was the strongest predicator of the need for multiple medications.
ALLHAT found that blacks and women exhibited more resistance. Black women had control rates of <60% and non-black men had the highest rate of adequate control (70%). The study also identified diabetes and residence in the southeastern United States as factors predicting the need for multiple antihypertensives. "We do not know why people living in the Southeast have higher rates of difficult-to-treat hypertension," Calhoun says. "Individuals in the region receive as much medication as patients in other parts of the country, eliminating the possibility of undertreatment. The rising prevalence of resistant hypertension underscores the need for physicians, particularly those in the ‘Stroke Belt,' to increase their awareness of blood pressure control."
Diagnosis
The guidelines emphasize the importance of distinguishing between true treatment-resistant hypertension, which represents an extreme phenotype, and uncontrolled high blood pressure, or pseudoresistance. "High blood pressure readings can be caused by poor medication adherence, which is not the same as treatment-resistant hypertension," Calhoun says. "Confirming treatment resistance is the first step in evaluating difficult-to-treat high blood pressure. In addition, patients with resistant hypertension often have other medical conditions that complicate management. If a secondary cause of hypertension is identified, such as obstructive sleep apnea, renal parenchymal disease, primary aldosteronism, or renal artery stenosis, treating these disorders, which may require referral to a specialist, can improve blood pressure control."
The white-coat effect and inaccurate blood pressure readings can contribute to the appearance of pseudoresistance. "Good blood pressure-taking techniques are critical to confirming resistant hypertension. Permitting patients to rest before taking readings and using appropriately sized cuffs can eliminate false measurements," says Calhoun, who strongly encourages patients with difficult-to-control hypertension to invest in a home blood pressure monitor.
"The use of home monitors engages patients in their health care and promotes awareness of blood pressure goals," he says. "Routine home blood pressure measurements provide a more accurate assessment of overall blood pressure and enhance physicians' ability to adjust medications."
The need for multiple medications exacerbates adherence issues, which can be compounded if multiple dosing schedules are necessary. Establishing a positive rapport with patients can foster education and promote productive conversations about therapeutic targets. "When physicians engage patients in their care, there is greater likelihood that individuals will discuss problems with a particular drug or regimen rather than stopping medications," Calhoun says. Simplifying drug regimens with combinations of long-acting agents can improve compliance.
Management
Patient management begins with confirmation of treatment-resistant hypertension, detection and correction of contributing lifestyle factors, and use of an efficient multitiered drug course. Weight loss, reducing dietary salt and alcohol, and increasing physical activity levels improve control of general hypertension and may improve control of resistant hypertension.
Management also should include re-moving or limiting interfering medications (particularly nonsteroidal antiinflammatories), treating secondary hypertensive conditions, and evaluating diuretic use. The guidelines emphasize the importance of diuretic therapy and note that treatment patterns reveal consistent underuse of diuretics. "When patients need more than two medications, one of them should be a diuretic," Calhoun says. Long-acting thiazides, chlorthalidone, or hydrochlorothiazide are effective. In patients with CKD physicians should consider furosemide or other loop diuretics.
Studies show combining two agents of different classes has an additive antihypertensive benefit. "Good data on triple-drug regimens are lacking, but our committee, based on members' clinical experience and the likelihood that combining drugs from several different classes will have a complementary effect, recommends a triple regimen that includes a thiazide diuretic, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a calcium channel blocker," Calhoun says.
Mineralocorticoid receptor antagonists (MRAs) have considerable antihypertensive effects when added to existing drug regimens. UAB is one of several centers to document the benefits of MRAs in management of hypertension. "Adding an MRA as a fourth-line agent is an appropriate consideration," he says, noting that concurrent MRA and thiazide diuretic use requires careful monitoring for evidence of hyperkalemia.
"Combination therapy must be personalized for each patient," says Calhoun, who notes that when a patient's blood pressure has not reached target goals after 6 months of treatment, physicians should strongly consider referral to a hypertension specialist. Treatment-resistant hypertension requires extensive medical management and multiple medications to achieve target blood pressure levels. "A specialist can conduct a thorough review of patients' medical histories and treatments, test for potentially reversible secondary causes of hypertension, and devise an individualized pharmacological regimen," he says.
For more information contact Dr. David Calhoun at 1-800-UAB-MIST or at mist@uabmc.edu
Resistant Hypertension:Diagnostic and Treatment Recommendations
Confirm Treatment Resistance
Office blood pressure >140/90 or >130/80 mm Hg in patients with diabetes or chronic kidney disease
and
Patient prescribed three or more antihypertensive medications at optimal doses, including if possible a diuretic
or
Office blood pressure at goal but patient requiring four or more antihypertensive medications
Exclude Pseudoresistance
Is patient adherent with prescribed regimen?
Obtain home, work, or ambulatory blood pressure readings to exclude white-coat effect.
Identify and Reverse Contributing Lifestyle Factors
Obesity
Physical inactivity
Excessive alcohol ingestion
High salt, low fiber diet
Discontinue or Minimize Interfering Substances
Nonsteroidal anti-inflammatory agents
Sympathomimetics (diet pills, decongestants)
Stimulants
Oral contraceptives
Licorice
Ephedra
Screen for Secondary Causes of Hypertension
Obstructive sleep apnea (snoring, witnessed apnea, excessive daytime sleepiness)
Primary aldosteronism (elevated aldosterone/renin ratio)
Chronic kidney disease (creatinine clearance <30 mL/min)
Renal artery stenosis (young female, known atherosclerotic disease, worsening renal function)
Pheochromocytoma (episodic hypertension, palpitations, diaphoresis, headache)
Cushing syndrome (moon facies, central obesity,
abdominal striae, interscapular fat deposition)
Aortic coarctation (differential in brachial and femoral pulses, systolic bruit)
Pharmacologic Treatment
Maximize diuretic therapy, including possible addition of mineralocorticoid receptor antagonist.
Combine agents with different mechanisms of action.
Use of loop diuretics in patients with chronic kidney disease and/or patients receiving potent vasodilators (eg, minoxidil).
Refer to Specialist
Refer to appropriate specialist for known or suspected secondary cause(s) of hypertension.
Refer to hypertension specialist if blood pressure remains uncontrolled after 6 months of treatment.