| Abstract|| |
Resistant hypertension affects approximately 10% of the hypertensive patient population. It should be differentiated from white-coat hypertension and pseudo-resistant hypertension. Non-compliance to anti-hypertensive therapy remains the most common cause of resistant hypertension. Primary hyperaldosteronism is not as uncommon as previously thought, but its prevalence depends on the selected population. Low-renin resistant hypertension responds to aldosterone blockade when other drugs are apparently inadequately effective. Sleep apnea syndrome can also contribute to the development of resistant hypertension by stimulating aldosterone secretion, which leads to vascular damage and may promote scarring through more direct actions. Normal blood levels of potassium in resistant hypertension do not exclude the possible presence of hyperaldosteronism.
Keywords: Resistant hypertension, Pseudo-Resistant Hypertension, Sleep Apnea, Aldosterone, Spironolactone,
|How to cite this article:|
Tamimi NA. Resistant Hypertension: A Methodological Approach to Diagnosis and Treatment. Saudi J Kidney Dis Transpl 2007;18:337-45
|How to cite this URL:|
Tamimi NA. Resistant Hypertension: A Methodological Approach to Diagnosis and Treatment. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2020 May 26];18:337-45. Available from: http://www.sjkdt.org/text.asp?2007/18/3/337/33748
| Introduction|| |
Resistant hypertension affects approximately 10% of the hypertensive patient population.  Although resistant hypertension affects a minority of treated hypertensive individuals, the resultant target organ damage is associated with a higher risk of cardiovascular events. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) defined resistant hypertension as "the failure to attain goal blood pressure (BP) in patients who are adhering to full doses of an appropriate three-drug regimen that includes a diuretic."  The 2003 European Society of Hypertension-European Society of Cardiology (ESH-ESC) guidelines for the management of arterial hypertension did not include diuretics in the definition but added that the therapeutic plan "includes attention to lifestyle measures".  Diagnosing a patient with resistant hypertension involves expensive investigations and referral to hospital clinicians to identify a secondary cause. This article aims to differentiate between true resistant hypertension, whitecoat hypertension and pseudo-resistant hypertension, as well as current management recommendations.
| White-coat resistant hypertension & pseudo-resistance|| |
Ambulatory BP monitoring provides information about the level and variability of BP. Although ambulatory BP is unreliable during exercise it reveals that in most cases average BP is lower than clinical BP. If BP is within the normal range, white-coat hypertension can be diagnosed.  Almost all studies relating the extent of cardiovascular damage to both clinic visit and ambulatory BP have demonstrated that ambulatory pressure correlates more closely with the extent of target organ damage than clinic pressure.
Ambulatory BP values are usually lower than clinical BP measurements. Awake individuals with hypertension have a mean BP of >130/85 mmHg, which decreases to <120/75 mmHg during sleep. In most individuals, BP decreases by 10%-20% during the night, and patients who do not experience such a decrease are at an increased risk for cardiovascular events. Blood pressure promptly increases with waking and getting up in the morning. The highest BP readings are usually observed between 0600 and 1200 hours, which tends to be the time of highest prevalence of many cardiovascular morbid events. The pattern of BP throughout the day is largely dependent on the pattern of activity. Blood pressure is usually higher during the working hours and lower during hours at home. Most experts recommend initiating treatment for hypertension when the average daytime ambulatory BP is above 140/90 mmHg. Few recommend treatment below 135/85 mmHg. 
Resistant hypertension should be differentiated from white-coat hypertension and pseudo-resistance. White-coat hypertension is characterized by an elevated office BP but a normal home or ambulatory BP recording and occurs in about 10% of the population.
White-coat hypertension has been defined as a persistently raised clinic visit BP together with normal daytime ambulatory BP.  In the recent American Heart Association recommendations for BP measurement in humans, white-coat hypertension was defined as a persistently elevated average office BP of >140/90 and an average awake ambulatory reading of <135/85 mmHg.  This type of hypertension can occur at any age and in both sexes and seems to be more common in patients over 60 years. Patients with white-coat hypertension do not necessarily exhibit any signs of anxiety and the increased BP is often not associated with tachycardia. It remains controversial whether it is necessary to start antihypertensive medications in patients with white-coat hypertension. The majority of clinicians do not favor drug treatment, as most studies have found that target organ damage such as left ventricular hypertrophy was less in white-coat hypertensive subjects as compared to true sustained hypertensive patients, thus indicating lower risk of morbidity.  It should be noted, however, that the PAMELA group found increased frequency in left ventricular mass index and left ventricular hypertrophy in white coat hypertensive patients compared to normotensive ones, suggesting that white coat hypertension is not an entirely harmless phenomenon. 
Some treated hypertensives show a whitecoat effect that results in an overestimation of their BP and underrates the response to pharmacological treatment.  This should be differentiated from white-coat hypertension whereby the office BP readings are high while normal at other times without drug therapy. Several factors may affect accurate measurements of BP: incorrect cuff size; physician-induced anxiety associated with measuring BP; recent meal; patient talking during BP measurement; drinking coffee and smoking.
Mezzetti et al evaluated resistant hypertension in 250 consecutive essential hypertension patients who had undergone ambulatory BP monitoring before assignment to treatment.  Seven (2.8%) patients had true resistant hypertension, whereas 20 (8.0%) patients showed a large white-coat effect. When one patient with sub-optimal treatment and three patients with non-compliance were excluded from the analysis, the exact prevalence of true resistant hypertension was reduced from 2.8% to 1.2%. The left ventricular mass index was measured in white-coat hypertensive patients and it was found to be significantly lower compared with truly resistant hypertensive patients, and similar to that in responders. Once patients are diagnosed with white-coat hypertension they will not require repeated urea, electrolyte and creatinine estimation, renal ultrasound scanning and in some cases renal arteriography. This is in addition to a reduction in consultation time, [Table - 1].
In pseudo-hypertension, the cuff pressure is inappropriately high compared with intraarterial pressure because of extensive atheromatous and/or medial hyperplasia in the arterial tree. The condition increases with age and diagnosis requires a high index of suspicion. Vidt  summarised the clinical clues that may guide the clinician to suspect the presence of pseudo-hypertension, [Table - 2]. Osler's maneuver, which is one clinical clue, is performed by inflating the BP cuff above the systolic BP. The maneuver is considered positive if a hard cord-like radial artery can still be palpated. Recommendations for methods for BP measurement in the clinic or office are shown in [Table - 3].
| Causes of resistant hypertension|| |
Non-compliance or non-adherence to sdrug therapy can be found in up to 50% of patients in some studies.  Sub-optimal therapy was identified as a cause in 43% of cases in one series.
This group also includes inappropriate combination of drugs such as the use of two drugs from the same class or two agents with the same or similar mechanism of action. In another series 53% of patients with resistant hypertension had their BP controlled to <140/90 mmHg largely from regimen optimization, intensification and proper use of diuretics. 
Volume overload is commonly observed in end-stage renal disease patients due to volume retention. Measurement of inferior vena cava diameter by ultrasound is the accepted noninvasive technique to determine volume status in dialysis patients.
Sleep apnea syndrome, unsuspected seconddary causes of hypertension, non-steroidal antiinflammatory drugs (NSAIDs), calcineurin inhibitors (cyclosporine and tacrolimus), oral contraceptives, corticosteroids, erythropoietin and liquorice, recreational drugs such as cocaine or amphetamines are among the possible causes of resistant hypertension.
| Recommended investigations for resistant hypertension|| |
- Routine biochemistry to include urea, electrolytes, serum creatinine and calcium.
- Thyroxin stimulating hormone (TSH) and thyroxin level.
- Urinalysis: clues for the presence of chronic kidney disease.
- 24-hour urine collection for creatinine clearance, catecholamine and venylmandelic acid (VMA) to assess the level of renal function and rule out pheochromocytoma.
- Plasma aldosterone concentration/ plasma renin activity (PAC/PRA) ratio to rule out primary aldosteronism.
- Chest X-ray.
- Renal ultrasound scan to assess chronic kidney disease and for indications for renovascular disease.
- Renal arteriogram to rule out renovascular disease, especially in high risk patients with diabetes mellitus and peripheral vascular disease.
| Sleep apnoea syndrome, resistant hypertension and the role of aldosterone|| |
Obstructive sleep apnea and hypertension are strongly associated, and the severity of obstructive sleep apnea correlates with the difficulty of controlling BP. Silverberg and Oksenberg point out that approximately 5060% of sleep apnea patients are hypertensive and approximately 50% of patients with hypertension have sleep apnea.  In another study, Logan et al diagnosed previously unrecognized sleep apnea in 83% of evaluated subjects with resistant hypertension, defined as poorly controlled despite using three or more different anti-hypertensive agents. The most frequently prescribed agents by drug class were diuretic (85%). Sleep apnea was more prevalent and more severe in men than women despite similarities in body mass index and age.  Several mechanisms for sleep apnea induced hypertension have been suggested. They include vascular stiffening, increased levels of circulating vasoconstrictors such as norepinephrine and endothelin, and sympathetic activation.
Two concepts have been proposed linking obesity to hypertension. One is the role of excessive sodium retention mediated by sympathetic nerve traffic to the kidneys, fat induced alterations in renal function, increased production of aldosterone, and/or the renal effects of increased insulin. The second theory is sympathetic nervous system activation mediated by fat itself or by repeated episodes of hypoxemia during sleep apnea. Aldosterone seems to be the potential point of convergence of these theories.  In a recent study using the Berlin questionnaire (designed to identify subjects at risk of having sleep apnea) in patients with resistant hypertension, it was found that subjects at high risk for sleep apnea were almost twice as likely to be diagnosed with primary hyperaldosteronism. The authors hypothesized that sleep apnea contributes to the development of resistant hypertension by stimulating aldosterone secretion. 
Primary hyperaldosteronism (bilateral idiopathic hyperaldosteronism and aldosteroneproducing adenoma) is rarely thought of as a common cause of hypertension in the general hypertensive population. In the past, clinicians would not consider the diagnosis of primary aldosteronism unless the patient presented with spontaneous hypokalemia and hence the prevalence rate was reported as less than 0.5% of hypertensive patients. However, recent studies suggest a prevalence as high as 30% in select hypertensive populations. Calhoun et al studied the prevalence of primary hyperaldosteronism among black and white subjects with resistant hypertension using suppressed plasma renin activity (<1.0 ng/ml per hour) and lack of suppression of urinary aldosterone (>12 µg/24 hour) during high dietary salt intake (>200 mmol/24 hour) as the diagnostic criteria. The overall prevalence in their study was 20% and the racial difference was not statistically significant, thus confirming that primary hyperaldosteronism is not an uncommon cause of resistant hypertension.  Plasma aldosterone concentration/ plasma renin activity (PAC/PRA) ratio is widely accepted as the screening test of choice for primary aldosteronism. This can be obtained while the patient is taking any anti-hypertensive drugs except spironolactone. 
Aldosterone promotes hypertension through sodium retention, which is a potential mechanism for both cardiac and renal injury. Several studies have demonstrated that the renin-angiotensin-aldosterone system is centrally involved in the progression of renal disease and heart failure. Aldosterone may enhance BP with consequent vascular damage and may promote scarring through more direct actions.  It is important to note that normal blood levels of potassium in resistant hypertension do not exclude the possible presence of hyperaldosteronism. This was shown in a study in which serum potassium was 4 ± 0.07 mmol/L and the introduction of spironolactone therapy normalized BP in all patients. It was used as a single therapy in 40% of the study group and in association with only one antihypertensive drug in the remaining 60%. 
In a recent large study involving 846 primary care patients with hypertension, 119 (14.1%) had an aldosterone renin ratio (ARR) > 800 pmol/l per ng/ml/h with normal plasma aldosterone, but only 1.8% had both plasma aldosterone > 400 pmol/L and ARR > 800. In 69 of the 119 (57%) patients who received spironolactone BP fell by 26/11 mmHg. These patients were normokalemic but had uncontrolled hypertension despite multiple drugs. The study concluded that primary hyperaldosteronism was an uncommon cause of hypertension but a much more common syndrome is that of low-renin resistant hypertension which responds to spironolactone when other drugs have been ineffective. 
Spironolactone has been the treatment of choice for primary hyperaldosteronism for many years. Recent studies have shown that a low dose of spironolactone provided significant additive BP reduction in subjects with resistant hypertension with and without primary aldosteronism.  However, due to its nonselectivity for the aldosterone receptor it is associated with side effects such as gynecomastia, impotence and menstrual irregularity. Recently, a competitive and selective aldosterone receptor antagonist, eplerenone, has become available for the treatment of essential hypertension and post-myocardial infarction heart failure reducing mortality in post-myocardial infarction heart failure by 15% when added to standard therapy. 
In conclusion, primary hyperaldosteronism is not uncommon and may be targeted with aldosterone antagonists or adrenalectomy in the case of adrenal adenoma.
| Management of resistant hypertension|| |
- Ensure compliance and motivation of the patient through appropriate education about the benefits of treatment, potential risks of not adequately controlled BP and the doses of the administered antihypertensive agents.
- Ensure that use of treatment regimen includes a diuretic: Outcome trials have shown that thiazide-based treatment regimens are more effective in preventing cardiovascular complications of hypertension, with the exception of the Second Australian National Blood Pressure Trial, which showed the superiority of angiotensin converting enzyme (ACE) inhibitors in men.  Despite all the evidence, thiazide diuretics remain underused and their use dropped markedly in the 1990s from 60% in 1990 to 38% in 1999. Patients with renal insufficiency usually respond better to loop diuretics. In selected patients with renal insufficiency, metolazone, a potent thiazide, can be combined with a loop diuretic to achieve optimum diuresis and control of volume overload.
- Review drug combinations; discussed in more detail in the next section.
- Re-assess the secondary causes of hypertension such as renovascular disease, especially in older patients. The presence of renal insufficiency, older age group, peripheral vascular disease, bruits, and diabetes mellitus provides clues to the presence of secondary causes of hypertension.
- Ensure that patients with hypertension and hypokalemia, and most patients with resistant hypertension undergo screening for primary hyper-aldosteronism with PAC/PRA ratio with or without captopril, an ACE inhibitor, administration.
- Ensure lifestyle modifications that are an important complement to the management plan. These include reduction of salt intake, smoking cessation, optimizing weight in overweight or obese individuals, avoidance of excessive alcohol intake, physical exercise, and increased fruit and vegetable intake.
- Consider adding aldosterone antagonists (monitor serum potassium). A recent study has shown that small doses of spironolactone 25-50 mg daily may provide significant additional BP reductions in patients resistant to drug combinations of other agents.  As side effects such as gynecomatsia and menstrual irregularities can be a limiting factor, a selective aldosterone antagonist may be used to achieve this goal.
| Drug combinations|| |
There are many effective combinations of anti-hypertensive medications currently available, which provide clinicians with a diverse selection. Drugs that block the renin angiotensin system are the beta-blockers, ACE inhibitors and angiotensin receptor blockers (ARBs). Despite their proven efficacy, these classes of drugs tend to be less effective in "low renin" states such as the elderly, Afro-Caribbean patients and patients with type II diabetes mellitus. However, recent evidence strongly supports using ARBs in type II diabetes mellitus. Therefore, the addition of an ACE inhibitor to a beta-blocker is unlikely to add much efficacy, as the beta-blocker will already have inhibited renin release.
The following combinations have been recommended by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure:
- ACE inhibitors and calcium channel blockers (CCBs).
- ACE inhibitors and diuretics
- ARBs and diuretics.
- Beta blockers and diuretics.
- Centrally acting drug and diuretic.
- Diuretic and diuretic: e.g. amiloride and hydrochlorothiazide.
| Conclusions|| |
Resistant hypertension is an uncommon form of hypertension. Causes for resistant hypertension are multi-factorial with nonadherence continuing to be the most common cause. Resistant hypertension needs to be differentiated from white-coat hypertension. Ambulatory BP monitoring provides valuable information about the level and variability of BP. Non-compliance or non-adherence to drug therapy as well as sub-therapeutic regimens or inappropriate drug combinations are important causes of resistant hypertension. Obstructive sleep apnea and resistant hypertension are also strongly associated. Recent studies suggest a high prevalence of primary hyperaldosteronism in selected hypertensive populations, and the presence of normal serum potassium does not rule out this diagnosis. The addition of small doses of aldosterone blockers may help to control blood pressure. A systemic approach to resistant hypertension may provide a cost effective assessment.
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Nihad A.M Tamimi
Pfizer Global Research & Development Ramsgate Road (IPC340) Sandwich CT13 9NJ
[Table - 1], [Table - 2], [Table - 3]