Resistant Hypertension: An Approach to Diagnosis and Treatment
ABSTRACT: Resistant hypertension—failure to reach target blood pressure in persons who adhere to an appropriate 3-drug regimen including a diuretic—is increasing in prevalence. This article reviews the diagnosis and treatment of resistant hypertension. It highlights situations, such as pseudohypertension, that may masquerade as resistance, and it identifies drugs that may aggravate blood pressure. It then reviews diseases (for example, obstructive sleep apnea) that are associated with resistant hypertension. Workup for secondary causes and specific therapy are suggested based on evidence.
Key words: resistant hypertension, pseudohypertension, white-coat hypertension, obstructive sleep apnea, chronic kidney disease, renal artery stenosis, aldosterone, Cushing disease, spironolactone
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Resistant hypertension is defined as a blood pressure (BP) above goal despite adherence to at least 3 different optimally dosed antihypertensives, one of which is a diuretic.1,2 A patient who has controlled BP while taking 4 or more medications is also considered to have resistant hypertension.1 According to data from the National Health and Nutrition Examination Survey, approximately 9% of US adult patients with hypertension meet criteria for resistant hypertension.3 These patients are at increased risk for cardiovascular disease, stroke, diabetes mellitus, and renal dysfunction,3 and they are also more likely to experience target organ damage.4 Because of the potential complications caused by elevated BP, it is important to identify reversible causes as well as those patients who may benefit from a specific therapeutic approach.5 An important consideration in making the diagnosis is to determine whether patients meet criteria for resistant hypertension or conversely if other reversible causes or pseudohypertension can be identified.5,6 A “checklist” should be reviewed to ensure accuracy in diagnosis (Table).
PSEUDORESISTANCE
“Pseudoresistant” hypertension may be caused by a number of reversible factors, including inaccurate BP measurement, non-optimized medication regimen, poor adherence, drug-induced causes, lifestyle factors, and the white-coat effect. These are all important factors to consider before diagnosing resistant hypertension.1,5,6
Blood pressure measurement. A possible cause of falsely elevated BP is poor BP measurement technique. If the patient is not allowed to rest or if an inappropriately small cuff is used, BP may be falsely elevated.5-7 Patients should be allowed to rest for at least 5 minutes with their back supported and arm at heart level prior to measurement.7 Using an inappropriately smaller cuff may result in elevations of systolic BP readings from 5 to 15 mm Hg.2 Smoking can also contribute to elevations of systolic pressure from 5 to 20 mm Hg; therefore, patients should be questioned about tobacco use.2 Averaging a minimum of 2 readings should be used as a representative of the patient’s BP.1,5,7
Antihypertensive medication regimen. Review the patient’s antihypertensive regimen. Appropriate medications should be chosen (based on compelling indications), and all medications should be optimally dosed before diagnosing resistant hypertension.2 Although limited data are available to guide therapy choices in those patients who are taking multiple antihypertensives, many patients have volume overload, which may warrant adding or increasing the dose of a diuretic.2Increasing the dose of or switching to a diuretic has been shown to be an effective approach to BP lowering in those patients being evaluated for resistant hypertension and will be discussed in more detail later.1,2,6,8-10 When determining which agents to choose, compelling indications should guide initial therapy. Further add-on medications should ensure inhibition of different pathogenic mechanisms for elevated BP as well as compensate for changes induced by other classes of medications included in the regimen.9 Potentially synergistic combinations are provided in the Table.
Nonadherence. A diagnosis of resistant hypertension is based on BP elevation despite adherence to a regimen of 3 medications at full doses; therefore, documenting adherence is an important component of the evaluation.1,2 Approximately 40% of patients with newly diagnosed hypertension will discontinue their antihypertensive medication within the first year of use.1,6,11 Potential side effects, cost, and complex regimens are some possible causes of nonadherence.5,12,13Ask patients how often they take their medication, and educate them about adverse effects and dosing.1
More frequent follow-up clinic visits that involve a multidisciplinary approach, patient maintenance of home BP measurements, and combination pills may improve adherence.1,2 Choosing antihypertensives that are to be administered once daily and with fewer side effects may also improve adherence.5,6
Drug-induced hypertension. Not only is it important to assess which medications patients are taking (or not taking) for hypertension, but it is also imperative to address medications that may aggravate hypertension or antagonize the effects of treatment. This detailed medication history should include all prescription and over-the-counter (OTC) medications, all herbal supplements, illicit drugs, all as-needed medications, and a detailed diet history that includes alcohol intake. Clinically, elimination of these medications may eliminate the need for unnecessary and costly treatments and tests.14-16
NSAIDs are commonly prescribed and may increase BP through the retention of salt and water and an increase in total peripheral vascular resistance.17 In addition, these agents may blunt the effect of certain antihypertensives such as diuretics, beta-blockers, and renin-angiotensin-aldosterone-system (RAAS) agents. While the NSAIDs vary in their effect on BP, some NSAIDs such as naproxen, indomethacin, and piroxicam are associated with the largest increase in BP and COX-2 selective agents such as celecoxib may be associated with a greater increase in BP.18-20 Patients may be switched to a more preferred analgesic such as acetaminophen; however, even this agent has been linked to an increase in BP in certain patients, such as those with coronary artery disease (CAD).21
Glucocorticoids may also increase BP in a dose-dependent fashion. This effect may be seen within 24 hours and may affect 20% of patients treated with these medications. This effect is usually eliminated by removing the drug; however, if treatment with glucocorticoids is necessary, a diuretic may be added to relieve the volume overload caused by steroid therapy.16
Antidepressants, such as the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine, have also been associated with increased BP. This effect is most likely due to its noradrenergic stimulation and is dose-dependent.22 Other agents such as tricyclic antidepressants, selegiline, and fluoxetine have also been noted to increase BP.16
Hormones such as oral contraceptives may also increase BP in approximately 5% of patients taking agents with high-dose estrogen (at least 50 mcg).23 This effect seems limited to oral contraceptives; postmenopausal hormone replacement therapy has minimal effect on BP.24 While BP elevation is usually minor, hypertensive crises may result. This is usually reversed on discontinuation of the drug, and women—specifically those with stage 2 hypertension—may see an improvement in BP control with the discontinuation of oral contraceptive agents.25
OTC medications such as decongestants (pseudoephedrine, phenylephrine, etc) and dietary supplements containing ephedra can also increase BP, making it important to ask patients about OTC agents and herbal supplements. Illicit drugs such as cocaine as well as stimulants such as amphetamines can also increase BP.16
Lifestyle factors. In addition to a detailed medication history, a detailed diet and social history should be obtained from the patient. First, a diet excessive in salt can contribute directly to increased BP and also blunt the effect of certain antihypertensives.26-28 Patients with chronic kidney disease (CKD), African Americans, and the elderly may be more sensitive to the effect of dietary salt.29 In any patient with hypertension, restriction of dietary intake of salt, in accordance with the Dietary Approaches to Stop Hypertension (DASH) diet, may provide a benefit. In addition to dietary salt, heavy alcohol intake can contribute to hypertension as well as resistance to antihypertensive therapy. As with salt intake, limitation of daily alcohol consumption (ideally less than 30 g/d) is a reasonable approach.1,16
Obesity is another lifestyle factor that should be evaluated in patients with resistant hypertension because obesity is related to an increased likelihood of hypertension, need for multiple antihypertensive medications, as well as the inability to control BP.1,30,31 For these patients, a diet and exercise program should be initiated with a goal of weight loss.
White-coat effect. Another concern prior to diagnosis of resistant hypertension is falsely elevated BP as a result of the white-coat effect (a persistently elevated clinic/office BP while out-of-office BP values are normal or significantly lower). This effect may be more common in patients with resistant hypertension and can be monitored through the use of out-of-office BP measurement (either home/self BP monitoring or ambulatory BP monitoring [ABPM]).32,33 ABPM refers to the measurement of BP at regular intervals (usually twice per hour) over a 24-hour period as the patient undergoes normal activities, including sleep, while home or self BP monitoring is less frequent and not scheduled. Twenty-four hour ABPM is the ideal method to perform this monitoring; however, home/self BP monitoring has also been shown to be effective and both options provide better prognostic value than office BP readings.34-37 Current United Kingdom guidelines recommend that the use of ABPM, or home BP readings in those intolerant of ABPM, be offered to all patients with a clinic BP higher than 140/90 mm Hg in order to confirm the diagnosis of hypertension.38 While ABPM has not become commonplace in the United States, its role in assisting in the diagnosis of white-coat effect is important. As a result, out-of-office BP readings, in addition to clinic readings, should be utilized in patients with resistant hypertension in order to rule out a white-coat effect.
Common conditions on next page
COMMON CONDITIONS ASSOCIATED WITH RESISTANT HYPERTENSION
Since a diagnosis of resistant hypertension is a critical prognostic and therapeutic milestone, it is imperative that BP and its prior treatment definitely fulfill criteria for the definition.39 Once the patient has been evaluated for the above criteria and after the diagnosis of resistant hypertension is verified, associated conditions and potential secondary causes should be considered. Six warrant further discussion: obstructive sleep apnea (OSA), chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD), renal artery stenosis (RAS), aldosterone excess, Cushing disease and other mineralocorticoid-driven resistant hypertension, and pheochromocytoma.
Obstructive sleep apnea. OSA is a syndrome, and its complications are not limited to the respiratory system. OSA independently increases fatal and non-fatal cardiovascular events by 2.87 and 3.17 times, respectively.40 Stroke in persons with OSA is 2.86 to 3.56 times more frequent than in those without. Since OSA is a syndrome accompanied by obesity, insulin resistance, and frequently diabetes, it should come as no surprise that it is associated with resistant hypertension. In fact, in a study of 41 consecutive patients with resistant hypertension, 83% later received a diagnosis of OSA.39,41 How should the diagnosis of OSA affect management of resistant hypertension? As will be detailed in the section on therapeutics, resistant BP in persons with OSA responds to a spironolactone-based regimen.39 In addition, spironolactone may also decrease the frequency of apneic episodes.42 Another specific treatment strongly recommended is utilization of an appropriately fitted continuous positive airway pressure (CPAP) apparatus. Although CPAP does not lower BP in all patients, select individuals may derive significant benefit.43
Chronic kidney disease and autosomal dominant polycystic kidney disease. Persons with resistant hypertension and stage 3 CKD (a glomerular filtration rate [GFR] of less than 60 cc/min.) should be evaluated for an etiology and referred to a nephrologist. Workup should include an ultrasound of the kidneys and an estimate of urine protein excretion.44 Not only is the association between CKD and resistant hypertension important, the combination is almost invariably complicated further by heart disease. This may influence antihypertensive choice, especially when left ventricular hypertrophy, ventricular remodeling, and systolic dysfunction are simultaneously present. These cardiac complications warrant regimens favoring angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and some form of beta blockade (either traditional beta-blockers or so-called beta-blockers “plus” such as carvedilol) (see below).
The renal portion of the illness may warrant ACEIs or ARBs based on elevations in urine protein excretion as seen with glomerular diseases, especially as a result of diabetes. On the other hand, agents that interfere with the RAAS (ACEIs, ARBs, and spironolactone) may cause hyperkalemia.
Since ADPKD is characterized by an earlier onset of hypertension, which also may be resistant, heart disease is a common accompaniment. Although BP control may not slow progression of the renal disease in ADPKD, it protects against prohibitive cardiovascular morbidity and mortality later in life.
Renal artery stenosis. RAS should be suspected with early or late onset of hypertension (that is, before age 30 or after age 55); accelerated hypertension or a hypertensive emergency; disparate kidney size on imaging; sudden or “flash” pulmonary edema; unexplained renal insufficiency; multivessel coronary or severe peripheral vascular disease; and unexplained heart failure.45 There is controversy regarding the need for additional diagnostic studies (renal angiography) and/or intervention (dilatation and stenting) for RAS in the setting of resistant hypertension.46 Recent research has demonstrated that percutaneous dilatation of RAS compared with medical therapy does not affect progression of underlying renal insufficiency.47 Furthermore, intervention was associated with a few, but nonetheless serious, complications. It is important to note, however, this study itself may have been underpowered and may have overrepresented individuals with unilateral RAS who were less likely to progress.45 Another randomized trial comparing intervention to medical therapy in the setting of RAS (Angioplasty and Stenting for Renal Artery Lesions [ASTRAL], n=806) reached similar conclusions, that is, medical therapy with antihypertensives is not inferior to intervention with a primary outcome of renal function and secondary outcomes of BP, time to renal or major cardiovascular events, and mortality.48-50 This study was criticized as well. A trial in progress, Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), may clarify the indications for interventions versus medical therapy with hypertension and renal insufficiency consequent to RAS.51
Pending results from the CORAL Study, the following summarizes situations wherein intervention may be superior to medical therapy for RAS, “Renal revascularization therapy is controversial; the only class I indication for renal revascularization under current guidelines is for hemodynamically significant atherosclerotic renal artery stenosis in the setting of recurrent, unexplained congestive heart failure (CHF) or sudden, unexplained pulmonary edema.”45
Aldosterone excess (including adrenal hyperplasia and adenoma). The best screening test for excess aldosterone in the setting of resistant hypertension is an aldosterone/renin ratio.52-53 Values warranting further investigation are a ratio of 30 to 1 or greater and an aldosterone level that exceeds 15 ng/dL. After the screening, further workup is subspecialty driven. Volume loading (for example, normal saline intravenously at a rate of 500 cc/hr for 4 hours) determines whether the elevated aldosterone can be suppressed by volume expansion. If not, the elevated aldosterone is autonomously secreted and likely to be secondary to either hyperplasia or adenoma. Volume depletion is also utilized in an effort to increase renin for the same reason. Furosemide in conjunction with a low-salt diet normally increases renin secretion. Renin will not rise with volume depletion maneuvers if autonomous aldosterone secretion is present. Differentiation between adenoma and hyperplasia may require selective adrenal aldosterone sampling to verify excess aldosterone on the side of a functioning adenoma. Surgery is indicated for an adenoma; spironolactone is effective for hyperplasia.
It is the authors’ bias that since spironolactone is efficacious in lowering BP in patients with resistant hypertension, even in persons without elevations in aldosterone and/or aldosterone/renin ratio, and since adrenal hyperplasia, opposed to adenoma, is successfully treated with spironolactone, that testing for autonomous aldosterone excess be pursued conservatively. Indications of an underlying adenoma—hypokalemia and metabolic alkalosis—warrant further investigation.
Cushing disease and other mineralocorticoid-driven resistant hypertension. When there is clinical suspicion of glucocorticoid excess based on physical examination findings and from screening laboratory values (striae, truncal obesity, and hyperglycemia, for example), it is reasonable to consider Cushing disease. Furthermore, acid-base and electrolyte values, specifically the presence of hypokalemic, metabolic alkalosis with hypertension, should lead to suspicion of underlying glucocorticoid, mineralocorticoid, or even “apparent” mineralocorticoid excess (licorice abuse or Liddle’s syndrome as examples). A guide to interpretation of electrolyte values and contributions of renin and aldosterone profiling to diagnosis is available.54 Analogous to screening for aldosterone excess, a similar philosophy is utilized for Cushing disease. Screening tests include collection of 24-hour urinary free cortisol or an overnight dexamethasone suppression test, and more recently, measuring salivary cortisol.55,56 Additional workup if screening is positive should solicit subspecialty advice. The mechanism leading to excess glucocorticoid secretion (pituitary, adrenal, or ectopic) requires additional study (for example, adrenocorticotropic hormone [ACTH] values).
Pheochromocytoma (only when they are clinical suspicions). Despite the lethal potential of a pheochromocytoma, the aforementioned etiologies are more commonly associated with resistant hypertension. Screening for pheochromocytoma should be reserved for those patients who do not have evidence of an alternative, more common cause or who have features consistent with catecholamine excess.
Treatment options on next page
TREATMENT OPTIONS FOR RESISTANT HYPERTENSION
A review of common practices that should be avoided is a reasonable place to begin. The following are examples of what not to do.
Do not keep adding medications. The definition of resistant hypertension clearly states that an appropriate and optimally dosed 3-drug regimen should suffice for BP control. Adding multiple additional drugs may not help and has the potential for serious side effects. An attempt to find an underlying cause and tailoring treatment for that cause, if possible, is necessary.
Do not combine an ACEI, an ARB, or a direct renin inhibitor. Any further reduction in BP is paltry at best with RAAS combination therapy and side effects may be prohibitive (renal failure and hyperkalemia).57,58 Studies in select populations with dual RAAS blockade, such as in persons with diabetes and proteinuric renal disease, were complicated by serious morbidity.59 In the words of Dr Messerli, “For the time being, given the adverse effects and lack of consistent survival benefits, the use of dual RAAS blockade should be avoided unless ironclad data emerge to the contrary.”57
Do not accept blood pressures that are not at target; there are still things that can be done. (Refer to the “Resistant Hypertension Checklist” provided in theTable). The following expand on 5 specific strategies for patients with resistant hypertension:
1. Revisit the initial regimen.
Patients often fail to reach therapeutic goals because of suboptimal therapy; therefore, it is important to revisit the initial regimen to determine if all agents are optimally dosed and if there may be better agents or improved combinations:
•Perform a “diuretic review.” The diuretic is the mainstay of the resistant patient’s medication regimen and should be optimized in order to see full therapeutic benefit.
Have you forgotten about chlorthalidone? When compared to the more commonly prescribed hydrochlorothiazide (HCTZ), chlorthalidone is more potent (50 mg of HCTZ is equivalent to approximately 25 to 37 mg of chlorthalidone) with a longer duration of action (16 to 24 hours for HCTZ vs 48 to 72 hours for chlorthalidone).60Taking advantage of these potency and pharmacokinetic differences may translate into better BP lowering if chlorthalidone is substituted for HCTZ. In addition, a recent, 23-year follow-up of a particular chlorthalidone cohort has determined chlorthalidone can be a “gift that keeps on giving”!61,62 Bottom line, 1 month of chlorthalidone use translates into 1 day of additional life.
If renal function is impaired (GFR of less than 50 cc/min), furosemide/loop diuretics may be a better option than thiazides for BP control. Because of furosemide’s shorter half-life, it is dosed twice daily.
•Question the value of hydralazine. What follows represents another authors’ bias. There are evidence-based medical questions regarding the value of hydralazine for BP control.63 Multiple Cochrane Database Reviews have questioned its use, specifically for hypertension, based on an absence of data regarding efficacy from randomized, controlled trials. Additionally, frequent dosing and adverse reactions may limit the use of this drug for essential hypertension. However, this criticism does not apply to its
robust indication for the treatment of systolic dysfunction in African Americans in combination with long-acting nitrates.
•Is the patient taking a beta-blocker? Could this agent be switched to a more potent antihypertensive medication? For patients with a compelling indication for a beta-blocker (CAD, CHF, etc), could the patient be switched to an optimal dose of a dual-acting beta-blocker such as carvedilol or labetolol (dual-acting beta- and alpha-blocker) in order to take advantage of the additional BP-lowering effects provided by alpha-blockade?
2. Switch to a regimen relying on a spironolactone backbone.
There have been multiple studies attesting to spironolactone’s efficacy in treating patients with resistant hypertension, especially those with OSA, and the authors consider spironolactone key in the treatment of resistant hypertension.39,64 One may ask, “Why add another medication to what is already a 3-drug combination?” The rationale is that the efficacy of spironolactone in resistant hypertension may permit some or all of the other medications to be discontinued. In fact, since a potential side effect of spironolactone is hyperkalemia, consider discontinuing the ACEIs/ARBs first (unless they have other indications such heart failure or diabetes!). The dose of spironolactone may be titrated upward, but serial potassium values should be monitored, especially in patients with CKD.
3. A possible non-medical option is inhibition of the sympathetic nervous system with renal denervation and baroreceptor interventions.65,66
Renal sympathetic nerves affect BP. In the 1950s, sympathectomy was done successfully to treat malignant hypertension. Today, selective renal sympathetic denervation, performed through a catheter delivering radiofrequency energy, has been demonstrated to lower BP and sustain that effect for at least 3 years. Long-term adverse events included transient ischemic attacks, hypertensive crises, hypotensive episodes, and angina. Thomas and colleagues66 at the Cleveland Clinic provide wise advice about the future of renal denervation therapies: “Given the well-known cardiovascular risks associated with uncontrolled hypertension, novel therapies such as renal denervation may provide an adjunct to existing pharmacologic approaches.”
A planned study named Symplicity HTN-3 will be the largest trial addressing renal denervation to date. Further data will either suggest superiority over medical interventions or not. The Cleveland Clinic article also reviews responses to denervation in specific cohorts with resistant hypertension including patients with left ventricular hypertrophy and diastolic dysfunction, OSA, and CKD. Also, the same paper provides references on carotid baroreceptor stimulation via an implantable device as another modality under preliminary study. It may provide another non-medical approach to control resistant hypertension.
4. Will there be other medical “resistant hypertension–specific” regimens?
In the short-term future, new agents and regimens for resistant hypertension may be available. New classes of agents currently being evaluated include the endothelin receptor antagonists.6 Endothelin is associated with potent vasoconstriction; therefore, blockade of endothelin receptors has been a mechanism under investigation.67 Darusentan, a selective endothelin receptor antagonist, has been associated with BP reduction in patients with resistant hypertension in randomized, double-blind, placebo-controlled trials.68,69 Preliminary studies have also combined spironolactone with chlorthalidone.70 The chlorthalidone add-on decreased sympathetic activity and augmented the effect of spironolactone.39 There has been some interest in judicious use of alpha-blockers as well.71 These latter suggestions are early and require further study.
5. Should minoxidil be a last resort?
Minoxidil is a potent vasodilator that must be accompanied by a beta-blocker and furosemide. It is difficult to use and fraught with many side effects (edema, anasarca, pericardial effusion, and hirsutism). However, it is still available and effective in select persons with resistant hypertension.72 Since it is used less frequently, its administration should be limited to physicians who are comfortable with dosing and side effects.
CONCLUSION
In summary, resistant hypertension is increasing in prevalence and puts the patient at risk for multiple complications. Prior to diagnosis, it is important to consider potential causes of “pseudohypertension.” The presence of an optimally dosed, appropriate 3-drug antihypertensive regimen should also alert the clinician to investigate possible reversible causes of hypertension. Once the above have been considered, it is important to take a close look at the drug regimen, ensuring all medications are appropriate and optimally dosed. Several treatment options are available, but spironolactone is currently the optimal add-on medication in patients with resistant hypertension; monitoring for hyperkalemia should be performed as the dose is titrated to effect.
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