Patient, male, 70 years old, with previous chronic kidney disease (stage 3) and dyslipidemia, was referred to the hypertension clinic to rule out refractory hypertension. He had a history of hypertension for 31 years, and his blood pressure was well controlled 5-6 years ago. Initial treatment medications were telmisartan, hydrochlorothiazide, and atenolol. Despite taking the drugs to the maximum dose, the patient’s blood pressure fluctuated at 185-210/90-100 mmHg. Aliskiren and amlodipine were subsequently added, but the blood pressure remained uncontrolled, and the patient later refused to take amlodipine because of the development of lower extremity edema.
The prescription was subsequently changed to: valsartan 160mg once a day; eplerenone 50mg twice a day; carvedilol 25mg twice a day; hydralazine 100mg three times a day; colistin 0,1mg twice a day; bumetanide 1mg once a day, but the home self-test blood pressure was still greater than 180/90mmHg. The patient did not take NSAIDs or plant additives, and the daily diet No salt was added to his daily diet, but he regularly ate at Italian restaurants and had no previous insomnia or snoring. 2006 routine renal angiogram did not show renal artery stenosis. He complained of good medication compliance and did not miss any medication prior to the outpatient visit.
The sitting and standing tests showed a sitting blood pressure of 180/90 mmHg and a heart rate of 59 beats/min; the standing blood pressure was 202/91 mmHg and a heart rate of 54 beats/min. All extremities had the same pulse, there was no ascites or jugular venous filling, non-sunken edema was present in both ankles, serum potassium was 3,5 mmol/L, and the estimated glomerular filtration rate (eGFR) was 48 mL/min/1,73 m2.
The patient’s blood potassium was at the low limit of normal and primary aldosteronism was considered; therefore, the patient’s medication was again adjusted prior to the diagnostic test for primary aldosteronism. Among the medications taken, those known to affect blood circulating renin and aldosterone levels were eplerenone, valsartan and bumetanide, which were discontinued and replaced with doxazosin, hydrazinoprazine and carvedilol, and colistin was continued. After 6 weeks of discontinuation of eplerenone, valsartan and bumetanide, a screening test for aldosteronism was performed.
The test revealed a significant increase in serum aldosterone to 52 ng/dL ( normal value <16 ng/dL, converted to pmol/L multiplied by 27, 75). Plasma renin activity was suppressed to a degree below the minimum detectable limit of 1 ng/mL/h (normal is 1 ng/mL/h). A saline loading test showed that serum aldosterone remained at 26 ng/dL, and an abdominal CT scan showed bilateral adrenal nodules of 8-10 mm in size with no signs of malignancy. However, venous blood sampling of the adrenal glands showed that the right adrenal aldosterone secretion was significantly greater than that of the left. The patient's blood pressure improved significantly after right adrenalectomy and could be controlled below 140/90 mmHg with just two medications.
Definition and onset of refractory hypertension
Refractory hypertension is defined by the JNC7 as blood pressure that does not reach 140/90 mm Hg despite the use of appropriate doses of antihypertensive medications including 3 or more (including 1 diuretic), and by the 2008 American Heart Association (AHA) position statement as blood pressure that is not controlled with at least 3 antihypertensive medications or controlled with at least 4 antihypertensive medications.
While the prevalence of refractory hypertension in the United States has not changed significantly over the past few decades, the prevalence of uncontrolled hypertension on more than 3 medications has nearly doubled, and among those treated for hypertension, the prevalence of refractory hypertension increased from 16% in 1998-2004 to 28% in 2005-2008.
The 2005-2008 National Health and Nutrition Examination Survey estimated that 13% of the treated and untreated hypertensive population met the JNC 7 definition of refractory hypertension and 21% of hypertensive patients met the AHA definition of refractory hypertension. Refractory hypertension has been found to increase cardiovascular disease and to be associated with emotional stress.
The pathogenesis of refractory hypertension remains unclear, but appears to be associated with multiple factors. Epidemiological studies have shown that advanced age, obesity, renal insufficiency, and diabetes mellitus are associated with refractory hypertension. Patients with refractory hypertension typically present with elevated systemic vascular resistance and expanded plasma volume but normal cardiac output. The mechanisms underlying this abnormal hemodynamic pattern remain unknown, but studies have found that most patients with refractory hypertension have elevated circulating aldosterone levels and suppressed plasma renin activity.
In this article, Wanpen Vongpatanasin from the University of Texas Southwestern Medical Center discusses the multiple factors associated with uncontrolled hypertension and analyzes the effectiveness of pharmacologic and nonpharmacologic interventions for refractory hypertension. The full article is published online in the June 4 issue of JAMA.
1. Assessment of white coat hypertension and pseudohypertension
1. 1 White coat effect
Before diagnosing refractory hypertension, clinicians must rule out the white coat effect and elevated blood pressure due to noncompliance with medications. A diagnosis of refractory hypertension based solely on an elevated office blood pressure may lead the clinician to make an incorrect diagnosis when home self-measured blood pressure or 24-hour ambulatory blood pressure is normal during treatment with antihypertensive medications. A recent study estimated that up to 30% of patients with elevated office BP treated with at least 3 antihypertensive medications had white coat hypertension, which is typically defined as an office BP ≥140/90 mmHg but a normal 24-hour ambulatory BP of 130/80 mmHg.
Several population-based studies have found that cardiovascular events in white-coat-effect individuals are lower than in patients with refractory hypertension and that their cardiovascular event rates are similar to those of hypertensive patients with well-controlled blood pressure. However, the prognosis of patients with white coat hypertension is worse than that of the normotensive population. Continuous home self-measurement of blood pressure or repeated ambulatory blood pressure monitoring is recommended for patients with white coat hypertension because follow-up
After 3-6 months, it is found that 20-25% of patients may progress to true refractory hypertension (office BP and 24-hour BP uncontrolled on at least 3 medications).
1,2 Poor compliance
Failure to take antihypertensive medications as prescribed is another cause of pseudo-refractory hypertension. Patient medication adherence can be monitored based on self-report, pill count, and prescription fill rate. The overestimated self-reported adherence was 80% higher than electronic monitoring of pill boxes (recording the date and time of pill box opening). Similarly, pill count monitoring adherence was only 50-70% as accurate as electronic pill box monitoring. In studies using questionnaire or pharmacy prescription data, medication nonadherence among patients with perceived refractory hypertension ranged from 8-40%.
When more sensitive serum drug monitoring techniques were used, medication nonadherence was 50-60%. Therefore, internists must be highly concerned about medication nonadherence when treating patients with refractory hypertension.
In the United States, serum levels of most antihypertensive medications in clinical settings are measured by laboratory tests, and the cost of these tests is covered by most health insurance plans. Electronic pill boxes are restricted to research institutions and are not yet used in the clinic.
Therefore, therapeutic drug serologic testing may be a viable option for compliance assessment when patients do not have a cartridge with them at the time of their visit or when pharmacies lack relevant data. Once medication nonadherence is established, every effort should be made to remove barriers to patient compliance. Reasons for poor patient compliance include side effects of antihypertensive medications (especially compounded medications), financial reasons, or cognitive impairment. Physicians should develop relevant plans and tailor them to patients in order to improve their compliance.
2. Lifestyle interventions
2. 1 Restrict sodium intake
Lifestyle improvements are recommended for all patients with refractory hypertension to lower blood pressure. Sodium intake is a major cause of refractory hypertension. A Meta-analysis of clinical trials found that restricting sodium intake by approximately 1.7 g per day resulted in a 5/3 mmHg reduction in office blood pressure in patients with mild uncomplicated hypertension, and the antihypertensive effect of sodium restriction was particularly significant in patients with refractory hypertension. One study found that sodium restriction to 1,1g per day
reduced 24-hour ambulatory blood pressure by 23/9 mmHg in patients with uncontrolled blood pressure (taking 3 antihypertensive drugs containing diuretics).
However, the daily sodium intake of Americans is much higher than the recommended level, reaching 8.5 g/d (the daily salt intake of Chinese residents is 10.6 g per capita). In the United States, about 75% of sodium intake comes from processed foods or restaurant foods. About 25% of sodium intake is obtained by adding it to food. Patients should be advised to read the nutritional labels of foods carefully as this is essential for sodium restriction and optimal blood pressure control.
2.2 Physical Activity
More than 40% of patients with refractory hypertension are not physically active. Guidelines recommend that people with hypertension get at least 30 minutes/day of aerobic exercise most days of the week. A recent randomized trial of patients with refractory hypertension showed that participation in a treadmill exercise program 3 times per week for 8-12 weeks significantly reduced ambulatory blood pressure by 6/3 mm Hg compared with sedentary patients. therefore, aerobic exercise should be encouraged in most patients with refractory hypertension.
3, secondary hypertension
Secondary hypertension accounts for 5-10% of all hypertension. However, many patients with secondary hypertension are more likely to have refractory hypertension than patients with uncomplicated hypertension. 30%-40% of patients with hypertension and 60%-70% of patients with refractory hypertension have combined obstructive sleep apnea. 5%-10% of patients with hypertension and 7%-20% of patients with refractory hypertension have primary aldosteronism.
3.1 Primary aldosteronism
Screening tests for primary aldosteronism include plasma renin activity tests and serum aldosterone levels. Both tests can be performed while the patient is taking most antihypertensive medications, but the test must be preceded by discontinuation of saline corticosteroid receptor antagonists and direct renin inhibitors, except in the case of saline loading tests to confirm post-aldosterone loading levels, which must be performed 2-3 weeks after discontinuation of diuretics, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, while saline corticosteroid receptor antagonists require 4-6 weeks.
Blood potassium should be maintained at 4 mmol/L as much as possible during the trial, because low potassium may affect aldosterone release and thus give false-negative results. During the trial, the patient’s antihypertensive regimen should be changed to a drug that has the least effect on the renin-angiotensin-aldosterone system, such as calcium channel blockers, hydrazopyridazine, and alpha blockers. Patients need to be followed closely during drug changes to prevent a sharp increase in blood pressure after withdrawal of antihypertensive drugs.
Patients with suppressed renin levels and elevated serum aldosterone (>15 ng/dL) should undergo a further saline loading test (2 L of intravenous saline over 4 hours) or other confirmatory test as recommended by the Endocrine Society. In patients with aldosterone levels ≤10 ng/dL after saline loading test, further adrenal venous blood sampling is required, and in these patients, CT or MRI of the adrenal glands alone cannot clearly differentiate bilateral idiopathic hyperplasia from unilateral aldosteronism. Patients with bilateral adrenal hyperaldosteronism should be given spironolactone or eplerenone. One study showed that patients with unilateral aldosteronism should undergo surgical unilateral adrenalectomy, which cures hypertension in 50-60% of patients.
3,2 Obstructive sleep apnea
Unlike primary aldosteronism, clinical trials have shown that treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) resulted in a slight decrease in blood pressure of about 3-5 mmHg in patients with refractory hypertension, but a decrease of 7-10 mmHg in patients who adhered to regular CPAP therapy. Hypertension, such as pheochromocytoma, Cushing’s syndrome, and hyperthyroidism, should be ruled out by hormone testing when relevant clinical manifestations are present. Certain medications such as birth control pills have also been associated with refractory hypertension.
Thus, a history of previous prescription and over-the-counter medication use has the potential to affect the effectiveness of antihypertensive medications or even directly elevate blood pressure.
3,3 Renal artery stenosis
Renal artery stenosis is another common cause of refractory hypertension, accounting for 2% to 24% of patients with refractory hypertension. Although several renal artery stenting devices have been approved by the FDA for clinical use, revascularization of the renal arteries for refractory hypertension remains controversial. In the largest trial to date, investigators enrolled 947 patients with refractory hypertension who had combined renal artery stenosis and found that renal artery stenting reduced systolic blood pressure by only 2 mmHg and did not improve cardiovascular or renal outcomes compared with optimal drug therapy.
These trials included patients with atherosclerotic renal artery stenosis, so stenting remains the treatment of choice for patients with hypertension associated with renal artery fibromuscular dysplasia. In addition, a recent large observational study found a greater benefit of blood pressure reduction with revascularization than with drug therapy in patients with refractory hypertension who had recently experienced a dramatic decline in renal function in combination with atherosclerotic renal artery stenosis, but these findings need to be further validated in a prospective randomized study.
4. Initiation of treatment for refractory hypertension
Diuretics should be initiated in the pharmacological management of hypertensive patients with uncontrolled blood pressure on 3 drugs. A prospective observational study of 3550 patients with refractory hypertension showed that diuretics improved blood pressure control at 1 year. Chlortalidone, a thiazide diuretic, is at least twice as potent as hydrochlorothiazide and is more effective than lenopril in reducing the risk of heart failure and stroke in black patients. Therefore, chlorothiazide may be considered as a starting treatment agent for patients with refractory hypertension.
The 2011 UK NICE Consensus Statement recommends indapamide over hydrochlorothiazide based on a Meta-analysis that found a stronger antihypertensive effect of indapamide (a thiazide diuretic). In contrast, the 2008 AHA position statement identified chlorothiazide as the only recommended diuretic, while the 2014 report from JNC8 did not specify any of the preferred thiazide diuretics as antihypertensive therapy. It is important to note that the JNC8 2014 report does not specifically address the treatment of refractory hypertension.
4.1 Angiotensin-converting enzyme inhibitors and calcium channel blockers
After optimizing the use of diuretics, patients with refractory hypertension should be treated with a combination of angiotensin-converting enzyme inhibitors and calcium channel blockers. The combination of these two drugs is superior to the combination of angiotensin-converting enzyme inhibitors and thiazide diuretics in reducing cardiovascular events in patients with high cardiovascular risk. A recent randomized clinical trial showed that the combination of an angiotensin II receptor blocker and a calcium channel blocker controlled 60% of patients who did not achieve target blood pressure despite previous use of three drugs (including diuretics).
Therefore, the combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker may be a reasonable alternative to starting treatment for refractory hypertension.
4,2 Salt corticosteroid receptor antagonists and α-blockers
Studies on fourth-line pharmacotherapy for refractory hypertension have not been extensively explored. In a recent randomized double-blind trial (ASPIRANT trial), spironolactone 25 mg/d reduced 24-hour ambulatory systolic blood pressure by 10 mmHg compared with placebo in 117 patients with refractory hypertension (on 3 diuretic-containing drugs). In a randomized study of refractory hypertensive patients with comorbid diabetes, the same reduction in ambulatory blood pressure was observed with the addition of spironolactone to the original 3 drugs (containing angiotensin inhibitors or angiotensin II blockers). An observational study also found that the addition of additional spironolactone rapidly suppressed left ventricular hypertrophy in patients with refractory hypertension.
Eplerenone is a more selective salt corticosteroid receptor antagonist without the anti-androgenic side effects of spironolactone, and its use as a fourth-line agent (50 mg twice daily) resulted in a 10 mmHg reduction in 24-hour ambulatory systolic blood pressure. spironolactone and eplerenone have hypotensive effects even at normal serum aldosterone levels.
Alpha-blockers are primarily used as an alternative to spironolactone, especially in patients undergoing screening tests for primary aldosteronism, because serum aldosterone levels are not affected by alpha-adrenergic receptors. In an observational analysis of a clinical trial containing 10,069 patients treated with amlodipine and perindopril or atenolol and bendroflumethiazide, respectively, the addition of additional doxazosin to either group resulted in a 12/7 mmHg reduction in blood pressure
without increasing the risk of heart failure. Unlike salt corticosteroid receptor antagonists. The combination of angiotensin II receptor blockers to the maximum dose of angiotensin-converting enzyme inhibitors resulted in only a mild decrease in blood pressure in patients with refractory hypertension. In a recent clinical trial in patients at high risk for vascular disease or diabetes mellitus, the combination of both increased the risk of syncope and renal insufficiency compared with the use of telmisartan or ramipril alone. Therefore, the combination of these two drugs should be avoided.
Similarly, the addition of the direct renin inhibitor aliskiren had no significant effect on blood pressure in patients whose blood pressure was not achieved with the combination of an angiotensin II receptor blocker and a diuretic. In addition, a recent study in diabetic patients found that aliskiren combined with an angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor increased the risk of hyperkalemia, renal insufficiency, and nonfatal stroke.
Beta-blockers should be used as fifth-line agents unless mandatory indications such as congestive heart failure or a history of prior myocardial infarction are present. Large clinical trials have found that the cardioprotective effect of beta-blockers combined with thiazide diuretics is weaker than that of calcium channel blockers combined with angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers combined with thiazide diuretics.
5. Device therapy for refractory hypertension
The sympathetic nervous system plays an important role in the development of primary hypertension and a variety of secondary hypertension, and devices for the treatment of refractory hypertension look at the sympathetic nervous system, but the success rate of these devices is inconsistent. In a randomized, double-blind, parallel-designed clinical trial (n=181), chronic electrical stimulation of the carotid sinus nerve (inhibition of the sympathetic nerve via a pressure-sensing reflex) by surgically implanted devices reduced blood pressure in 54% of patients with refractory hypertension but similarly improved it in 46% of control patients (n=81), thus finding device treatment ineffective (P=0,97), but the associated cause is not known.
Transcatheter renal sympathetic nerve ablation is another treatment strategy for refractory hypertension. This technique uses radiofrequency energy to ablate sympathetic nerves in the outer membrane of the renal artery. Although an early trial of this technique alone found promising results, a subsequent randomized, sham-operated controlled trial (SIMPLICITY-HTN3) found little effect on in-office blood pressure and 24-hour ambulatory blood pressure. Whether renal sympathetic ablation is beneficial in patients with refractory hypertension remains unclear.
6. Conclusion
The treatment of refractory hypertension, especially in patients taking 5 or more medications, remains challenging. The choice to increase antihypertensive medication should not be based solely on the effectiveness of the drug, but also on the corresponding increase in cost, drug side effects, and potential cardiovascular benefits. Among patients with uncontrolled hypertension on 3 or more antihypertensive medications, 50% are on suboptimal doses, and less than 5% of patients in the United States are given a salt corticosteroid receptor antagonist. Therefore, antihypertensive drug prescriptions should be optimized before extensive screening for secondary hypertension.