News Author: Steve Stiles
CME Author: Charles Vega, MD
A new statement from the American Heart Association zeroes in on a group it says may make up 20% to 30% of patients with hypertension but has received only limited attention in formal guidelines, probably because they have been targeted in few clinical trials [1]. The document defines the group, patients with “resistant” hypertension, as those whose blood pressure (BP) remains above goal despite concurrent therapy with three distinct agents or who need at least four such drugs to achieve control.
Writing committee chair Dr David A Calhoun (University of Alabama at Birmingham) observed for heartwire that the document, the first of its kind, is “based largely on expert consensus, mainly because as a group, these patients have not been studied separately.” He and his colleagues hope that it will, among other things, encourage the development of clinical trials specifically for resistant hypertension.
The statement, which provides guidelines for patient workup and therapy, was published online in Hypertension on April 7, 2008 and is slated for the journal’s June issue.
Evaluation of patients who don’t respond to a regimen consisting of three agents from different drug classes, such as a diuretic, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, and a calcium-channel blocker, should be directed at “confirming true treatment resistance.” It usually has multiple causes, according to the statement, and requires the exclusion of “pseudoresistance,” managing lifestyle-related causes, and looking for possible underlying etiologies.
Pseudoresistance, the document says, involves the perception of treatment resistance due to such causes as poor patient adherence to therapy (one of the leading causes of uncontrolled BP), incorrect blood-pressure readings (the result, usually, of poor BP-measurement technique on the provider’s part), or a “white-coat” effect.
“White-coat hypertension is as common in these patients as it is in the general population,” Calhoun said, and is behind about one-fifth of cases of apparent resistant hypertension. Ambulatory blood-pressure monitoring may be necessary for an accurate diagnosis, according to the document.
Modifiable “lifestyle factors” that can be associated with resistant hypertension, it says, include obesity, dietary salt intake, and alcohol use.
Similarly, a number of noncardiac drugs and similar substances can raise BP and “should be avoided or withdrawn.” They include selective cyclooxygenase-2 (COX-2) inhibitors and traditional nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin; amphetamines; oral contraceptives; erythropoietin; and even natural licorice and some herbal medications such as ephedra.
Then there should be a search for underlying secondary causes of treatment resistance, which as a workup strategy “is probably not as common as it should be,” Calhoun said. Such causes can include obstructive sleep apnea, diabetes, pheochromocytoma, Cushing’s syndrome, renal parenchymal disease, renal artery stenosis, and primary aldosteronism.
Primary aldosteronism, in particular, “seems to be particularly common in patients with resistant hypertension,” according to Calhoun; the document says it is present in perhaps 20% of cases. But interestingly, “we and others have shown that even in the absence of true primary aldosteronism, aldosterone blockade can often be effective,” he said.
“We feel it is important to screen for classic primary aldosteronism, and if that evaluation is negative, the patient may still benefit from aldosterone antagonists,” even if aldosterone levels are normal, Calhoun said.
Measures related to drug therapy include determining whether diuretic dosing is optimal, “maximizing adherence,” and encouraging patients to take at least one of their antihypertensives at bedtime, and then making any necessary changes. A “lack of or underuse of diuretic therapy,” the document says, has been a consistent finding in studies of patients seen at hypertension specialty clinics. And, as complex dosing regimens are associated with poor compliance, “prescribed regimens should be simplified as much as possible.”
A complete list of the financial relationships disclosed by the authors and reviewers is available in the original study article.
Source
Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; DOI: 10.1161/HYPERTENSIONAHA.108.189141. Available at http://hyper.ahajournals.org.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Clinical Context
Resistant hypertension is defined as BP that remains above goal levels despite the concurrent use of at least 3 antihypertensive medications of different classes. While the exact prevalence of resistant hypertension is unknown, clinical trials of patients with hypertension suggest rates of 20% to 30%. Also, the prognosis of resistant hypertension has not been specifically evaluated, but these patients are thought to be at higher cardiovascular risk due to a higher rate of concomitant conditions such as diabetes, obstructive sleep apnea, and chronic kidney disease.
The current scientific statement from the American Heart Association examines patient factors that promote resistant hypertension as well as management strategies for resistant hypertension.
Study Highlights
Systolic BP is more often uncontrolled vs diastolic BP in cases of resistant hypertension. Older age, a high baseline BP, obesity, excessive dietary salt ingestion, chronic kidney disease, diabetes, and left ventricular hypertrophy increase the risk for resistant hypertension. Black race, female sex, and living in the southeastern United States also increase the risk for resistant hypertension.
Genetic assessments of patients with resistant hypertension have been limited.
Poor BP technique and poor adherence to antihypertensive medications can mimic true resistance to therapy. During 5 to 10 years of follow-up, less than 40% of patients may remain adherent to antihypertensive treatment.
Medications that may promote resistant hypertension include NSAIDs, sympathomimetic agents such as diet pills and decongestants, oral contraceptives, and erythropoietin. Acetaminophen can also promote mild elevations of BP but to a much lesser extent than NSAIDs. Therefore, acetaminophen is preferred over NSAIDs for pain among patients with hypertension.
Secondary causes of hypertension are more common in older patients.
Sleep apnea was diagnosed in 83% of one series of patients with resistant hypertension of unknown etiology. Sleep apnea appears to affect BP more severely in men vs women, but the exact mechanism of how sleep apnea worsens hypertension is not well-elucidated.
Primary aldosteronism may be present in 20% of patients with resistant hypertension, and these patients frequently have normal levels of serum potassium.
Cushing’s syndrome may promote target organ damage beyond what could be expected from the elevation of BP alone. The most effective treatment of Cushing’s syndrome is a mineralocorticoid receptor antagonist.
Some research has suggested that renal artery stenosis is the most common cause of secondary hypertension among older adults. More than 90% of renal artery stenoses are atherosclerotic in origin.
Routine evaluation of patients with treatment-resistant hypertension should include a metabolic profile, urinalysis, and paired morning plasma renin or plasma renin activity plus aldosterone levels. Abdominal computed tomography imaging to evaluate for adrenal adenomas is not recommended because of poor specificity.
Managing resistant hypertension includes adherence to using combination agents and once-daily dosing, weight loss, and dietary salt restriction. Salt restriction can reduce systolic BP by 5 to 10 mm Hg and diastolic BP by 2 to 6 mm Hg.
Some trials have shown a reduction in BP linked with the use of continuous positive airway pressure (CPAP) for obstructive sleep apnea, but other research suggests that CPAP is less effective.
Angioplasty of fibromuscular renal artery stenosis almost always benefits BP levels, but restenosis can occur 20% of the time.
Among specific classes of antihypertensive medications, diuretics are the most useful in the management of resistant hypertension. Chlorthalidone is preferred over hydrochlorothiazide because of superior efficacy.
Medications that antagonize mineralocorticoid receptor actions, such as spironolactone or amiloride, can further reduce BP among patients receiving multiple antihypertensive medications. These medications appear generally safe and well tolerated.
Dosing some antihypertensive medications at night may reduce BP to a greater degree than dosing during daylight hours only.
Limited research exists regarding ideal combinations of antihypertensive medications for patients with resistant hypertension.
Pearls for Practice
Routine evaluation of patients with treatment-resistant hypertension should include a metabolic profile, urinalysis, and paired morning plasma renin or plasma renin activity plus aldosterone levels. Abdominal computed tomography imaging to evaluate for adrenal adenomas is not recommended because of poor specificity.
Among specific classes of antihypertensive medications, diuretics are the most useful in the management of resistant hypertension.
Reviewed by Dr. Ramaz Mitaishvili
