Hypertension

Hemodynamics and physiologic components (eg, plasma volume, activity of the renin-angiotensin system) vary, indicating that primary hypertension is unlikely to have a single cause. Even if one factor is recognized, multiple factors are probably involved in sustaining elevated blood pressure (the mosaic theory). Heredity is a predisposing factor, but the exact mechanism by which genetics plays a role is unclear. At younger ages, environmental factors (eg, dietary sodium, stress) seem to affect only people who are genetically susceptible; however, in patients > 65 years, high sodium intake becomes more likely to precipitate hypertension.

Common causes include (1)

• Obstructive sleep apnea

• Renal parenchymal disease: Chronic glomerulonephritis or pyelonephritis, polycystic renal disease, lupus nephritis, obstructive uropathy

• Renovascular disease

• Primary aldosteronism (2)

• Other endocrine disorders (less common): Pheochromocytoma, Cushing syndrome, congenital adrenal hyperplasia, hyperthyroidism, hypothyroidism (myxedema), primary hyperparathyroidism, acromegaly, and mineralocorticoid excess syndromes other than primary aldosteronism

• Prescription or over-the-counter medications: Sympathomimetics (decongestants), nonsteroidal anti-inflammatory drugs (NSAIDs), antipsychotics, tyrosine kinase inhibitors, angiogenesis inhibitors, stimulants, corticosteroids, cocaine

• Vascular anomalies: Coarctation of the aorta

Licorice may contribute to worsening of blood pressure control. Diabetes is not considered a cause of secondary hypertension, although patients with diabetes commonly also are hypertensive.

1. 1. Rimoldi SF, Scherrer U, Messerli FH: Secondary arterial hypertension: when, who, and how to screen? Eur Heart J 35(19):1245–1254, 2014. doi:10.1093/eurheartj/eht534

2. 2. Brown JM, Siddiqui M, Calhoun DA, et al: The unrecognized prevalence of primary aldosteronism: A cross-sectional study. Ann Intern Med 173(1):10–20, 2020. doi:10.7326/M20-0065

In many cases of hypertension, sodium transport across the vascular cell membrane is abnormal, because the sodium-potassium pump (Na+, K+-ATPase) is defective or inhibited, or because permeability to sodium ions is increased. The result is increased intracellular sodium and calcium, which makes the cell more sensitive to sympathetic stimulation. Because Na+, K+-ATPase may pump norepinephrine back into sympathetic neurons (thus inactivating this neurotransmitter), inhibition of this mechanism could also enhance the effect of norepinephrine, increasing BP. Defects in sodium transport may occur in children who are normotensive but have a parent with hypertension.

Sympathetic stimulation increases blood pressure, usually more in patients with hypertension than in patients who are normotensive. Whether this hyperresponsiveness resides in the sympathetic nervous system or in the myocardium and vascular smooth muscle is unknown.

A high resting pulse rate, which may result from increased sympathetic nervous activity, is a well-known predictor of hypertension.

In some patients with hypertension, circulating plasma catecholamine levels during rest are higher than normal.

The renin-angiotensin-aldosterone system helps regulate blood volume and therefore blood pressure. Renin, an enzyme formed in the juxtaglomerular apparatus, catalyzes conversion of angiotensinogen to angiotensin I. This inactive product is cleaved by angiotensin-converting enzyme (ACE), mainly in the lungs but also in the kidneys and brain, to angiotensin II, a potent vasoconstrictor that also stimulates autonomic centers in the brain to increase sympathetic discharge and stimulates release of aldosterone and vasopressin. Aldosterone causes sodium retention and vasopressin causes water retention, elevating BP. Aldosterone also enhances potassium excretion; low plasma potassium (< 3.5 mEq/L [< 3.5 mmol/L]) increases vasoconstriction through closure of potassium channels.

Renin secretion is controlled by at least 4 mechanisms, which are not mutually exclusive:

• A renal vascular receptor responds to changes in tension in the afferent arteriolar wall

• A macula densa receptor detects changes in the delivery rate or concentration of sodium chloride in the distal tubule

• Circulating angiotensin II has a negative feedback effect on renin secretion

• Sympathetic nervous system stimulates renin secretion mediated by beta-receptors (via the renal nerve)

Elevated angiotensin II levels are generally acknowledged to be responsible for renovascular hypertension, at least in the early phase, but the role of the renin-angiotensin-aldosterone system in primary hypertension is not established. However, in patients with African ancestry and older patients with hypertension, renin levels tend to be low (1). Older patients also tend to have low angiotensin II levels, which may be related to a more volume-dependent salt-sensitive form of hypertension.

Hypertension due to chronic renal parenchymal disease (renoprival hypertension) results from the combination of a renin-dependent mechanism and a volume-dependent mechanism. In most cases, increased plasma renin activity is not evident. Hypertension is typically moderate and sensitive to sodium and water balance.

Deficiency of a vasodilator (eg, bradykinin, nitric oxide), rather than excess of a vasoconstrictor (eg, angiotensin, norepinephrine), may cause hypertension. Reduction in nitric oxide, due to stiff arteries, occurs with aging, and this reduction contributes to salt sensitivity (ie, lesser amounts of salt ingestion will raise BP) (2). With reduced nitric oxide, a large sodium load (eg, a salty meal) may increase systolic BP by > 10 to 20 mm Hg.

If the kidneys do not produce adequate amounts of vasodilators (because of renal parenchymal disease), blood pressure can increase.

Vasodilators and vasoconstrictors (mainly endothelin) are also produced in endothelial cells. Therefore, endothelial dysfunction greatly affects blood pressure.

No pathologic changes occur early in hypertension. Severe or prolonged hypertension damages target organs (primarily the cardiovascular system, brain, and kidneys), increasing risk of

• Coronary artery disease (CAD) and myocardial infarction (MI)

• Heart failure

• Stroke (particularly hemorrhagic)

• Renal failure

• Death

Elevated BP levels lead to the development of generalized arteriolosclerosis and acceleration of atherogenesis. Arteriolosclerosis is characterized by medial hypertrophy, hyperplasia, and hyalinization of small arteries (arterioles), notably in the eyes and the kidneys. In the kidneys, the changes narrow the arteriolar lumen, increasing TPR; thus, hypertension leads to more hypertension. Furthermore, once arteries are narrowed, any slight additional shortening of already hypertrophied smooth muscle reduces the lumen to a greater extent than in normal-diameter arteries. These effects may explain why the longer hypertension has existed, the less likely specific treatment (eg, renovascular surgery) for secondary causes is to restore blood pressure to normal. Thus, earlier diagnosis and treatment of even modestly elevated BP (ie, systolic BP of 120 to 129 mm Hg, even if the diastolic BP is in normal range) may provide benefit, especially in younger patients with a family history of hypertension.

Because afterload is increased in patients with elevated BP, the left ventricle gradually hypertrophies, causing diastolic dysfunction. The ventricle eventually dilates, causing dilated cardiomyopathy and heart failure, often worsened by arteriosclerotic coronary artery disease. Thoracic aortic dissection is typically a consequence of hypertension; almost all patients with abdominal aortic aneurysms have hypertension.

1. 1. Williams SF, Nicholas SB, Vaziri ND, Norris KC. African Americans, hypertension and the renin angiotensin system. World J Cardiol 6(9):878-889, 2014. doi:10.4330/wjc.v6.i9.878

2. 2. Fujiwara N, Osanai T, Kamada T, et al: Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: modulation of nitric oxide synthesis by salt intake. Circulation 101:856–861, 2000.

1. 1. Matsuoka S, Kaneko H, Okada A, et al. Association of retinal atherosclerosis assessed using Keith-Wagener-Barker system with incident heart failure and other atherosclerotic cardiovascular disease: Analysis of 319,501 individuals from the general population. Atherosclerosis 2022;348:68-74. doi:10.1016/j.atherosclerosis.2022.02.024

The blood pressure used for formal diagnosis should be an average of 2 or 3 measurements taken in the office at different times under these conditions:

• Patient seated in a chair (not examination table) for > 5 minutes, feet on floor, back supported

• Upper limb supported at heart level with no clothing covering the area of cuff placement

• No exercise, caffeine, or tobacco use for at least 30 minutes

At the first visit, measure BP in both arms; subsequent measurements should use the arm that gave the higher reading.

A properly sized BP cuff is applied to the upper arm. An appropriately sized cuff covers two-thirds of the biceps; the bladder is long enough to encircle > 80% of the arm, and bladder width equals at least 40% of the arm’s circumference. Thus, patients with obesity usually require large cuffs. The clinician inflates the cuff above the expected systolic pressure and gradually releases the air while listening with a stethoscope placed over the brachial artery. As the pressure falls, the pressure at which the first heartbeat is heard is systolic BP. Total disappearance of the sound marks diastolic BP. The same principles are followed to measure BP in a forearm (radial artery) and thigh (popliteal artery). Mechanical devices should be calibrated periodically. Fully automated oscillometric devices may provide accurate BP measurements and reduce human error (1).

BP is measured in both arms because BP that is > 15 mm Hg higher in one arm than the other requires evaluation of the upper vasculature.

BP is measured in a thigh (with a much larger cuff) to exclude coarctation of the aorta, particularly in patients with diminished or delayed femoral pulses; with coarctation, BP is significantly lower in the legs than in the arms.

White coat hypertension is defined as BP that is elevated in the office but does not meet the criteria for hypertension based on out-of-office readings in untreated patients. The prevalence is approximately 10 to 20% of the population and is more common in children, older adults, and women, as well as those with office-based BP close to the diagnostic threshold.

White coat effect refers to BP that is elevated in the office but is normal during out-of-office readings, among patients who are on treatment for hypertension.

The data about treatment outcomes of patients with white coat hypertension are conflicting. Untreated white coat hypertension seems to be associated with more adverse cardiovascular outcomes compared to normotension. Patients with white coat hypertension have a 3- to 4-fold increased risk of developing sustained hypertension after 7 to 10 years compared to normotensive people (2). White coat effect does not appear to be associated with adverse cardiovascular outcomes.

Masked hypertension is defined as blood pressure that is consistently elevated outside the office, but in which office readings do not meet the criteria for hypertension in untreated people. This group of patients may represent 10 to 30% of the adult population and is more common in men, non-Hispanic Black people, and people with diabetes (3).

Masked hypertension and masked uncontrolled hypertension (in those being treated) are associated with increased cardiovascular risk, with mortality similar to the risk in patients with sustained hypertension (4).

Home or ambulatory BP monitoring is indicated when white coat hypertension or masked hypertension is suspected.

The history includes the

• Duration of hypertension and previously recorded BP levels

• History or symptoms of coronary artery disease, heart failure, or obstructive sleep apnea

• Symptoms of, or personal or family history of, other relevant coexisting disorders (eg, stroke, renal dysfunction, peripheral arterial disease, dyslipidemia, diabetes, gout)

• Use of medications that predispose to hypertension (eg, NSAIDs, estrogen-containing oral contraceptives)

• Sleep duration

Social history includes exercise levels and use of tobacco, alcohol, and stimulants (including medications and illicit drugs).

A dietary history focuses on intake of salt and stimulants (eg, tea, coffee, caffeine-containing sodas, energy drinks).

The physical examination includes measurement of height, weight, and waist circumference; fundoscopic examination for retinopathy; auscultation for bruits in the neck and abdomen; and a full cardiac, respiratory, and neurologic examination. The abdomen is palpated for kidney enlargement and abdominal masses. Peripheral arterial pulses are evaluated; diminished or delayed femoral pulses suggest aortic coarctation, particularly in patients < 30 years. A unilateral renal artery bruit may be heard in thin patients with renovascular hypertension.

After hypertension is diagnosed based on blood pressure measurements, testing is needed to

• Detect target-organ damage

• Identify cardiovascular risk factors

The more severe the hypertension and the younger the patient, the more extensive is the evaluation. Tests may include

• Urinalysis and urinary albumin:creatinine ratio; if abnormal, consider renal ultrasound

• Lipid panel, complete metabolic panel (including creatinine or cystatin C, potassium, and calcium), fasting plasma glucose

• ECG

• Sometimes measurement of thyroid-stimulating hormone

• Sometimes measurement of plasma free metanephrines (to detect pheochromocytoma)

• Sometimes a sleep study

Depending on results of the examination and initial tests, other tests may be needed.

Renal ultrasound to evaluate kidney size may provide useful information if urinalysis detects albuminuria (proteinuria), casts, or microhematuria, or if serum creatinine or cystatin C is elevated.

Patients with hypokalemia unrelated to diuretic use are evaluated for high salt intake and for primary aldosteronism by measuring plasma aldosterone levels and plasma renin activity. The prevalence of primary aldosteronism is higher than previously recognized, occurring in approximately 10 to 20% of patients with resistant hypertension (5, 6).

On ECG, a broad, notched P-wave indicates atrial hypertrophy and, although nonspecific, may be one of the earliest signs of hypertensive heart disease. Elevated QRS voltage, with or without evidence of ischemia, may occur later and indicates left ventricular hypertrophy (LVH). When LVH is seen on ECG, echocardiography is often done.

If coarctation of the aorta is suspected, echocardiography, chest CT, or MRI can confirm the diagnosis.

Patients with labile, significantly elevated BP and symptoms such as headache, palpitations, tachycardia, excessive perspiration, tremor, and pallor are screened for pheochromocytoma by measuring plasma free metanephrines and for hyperthyroidism, first by measuring thyroid-stimulating hormone (TSH).

A sleep study should be strongly considered in patients whose history suggests sleep apnea.

Left Ventricular Hypertrophy on ECG

Image

© Springer Science+Business Media

Patients with symptoms suggesting Cushing syndrome, systemic rheumatic diseases, eclampsia, acute porphyria, hyperthyroidism, myxedema, acromegaly, or central nervous system (CNS) disorders also require further evaluation.

1. 1. Muntner P, Shimbo D, Carey RM, et al: Measurement of blood pressure in humans: A scientific statement from the American Heart Association. Hypertension 73:e35–e66, 2019.

2. 2. Cohen JB, Lotito MJ, Trivedi UK, Denker MG, Cohen DL, Townsend RR: Cardiovascular events and mortality in white coat hypertension: A systematic review and meta-analysis. Ann Intern Med 170(12):853–862, 2019. doi:10.7326/M19-0223

3. 3. Wang YC, Shimbo D, Muntner P, Moran AE, Krakoff LR, Schwartz JE: Prevalence of masked hypertension among US adults with nonelevated clinic blood pressure. Am J Epidemiol 185(3):194–202, 2017. doi:10.1093/aje/kww237

4. 4. Pierdomenico SD, Pierdomenico AM, Coccina F, et al: Prognostic value of masked uncontrolled hypertension. Hypertension 72(4):862–869, 2018. doi:10.1161/HYPERTENSIONAHA.118.11499

5. 5. Burrello J, Monticone S, Losano I, et al: Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit. Hypertension 2020;75(4):1025-1033. doi:10.1161/HYPERTENSIONAHA.119.14063

6. 6. Mulatero P, Stowasser M, Loh KC, et al: Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89(3):1045-1050. doi:10.1210/jc.2003-031337

Lifestyle modifications are recommended for all patients with elevated BP or any stage hypertension (4). The best proven nonpharmacologic interventions for prevention and treatment of hypertension include the following:

• Increased physical activity, ideally with a structured exercise program

• Weight loss, if appropriate

• Healthy diet rich in fruits, vegetables, whole grains, and low-fat dairy products, with reduced saturated and total fat content

• Reduced dietary sodium, optimally to < 1500 mg/day (< 3.75 g sodium) , but at least a 1000 mg/day reduction

• Enhanced dietary potassium intake, unless contraindicated due to chronic kidney disease or use of medications that reduce potassium excretion

• Moderation in alcohol intake in those who drink alcohol to ≤ 2 drinks daily for men and ≤ 1 drink daily for women (one drink is about 12 oz of beer, 5 oz of wine, or 1.5 oz distilled spirits)

• Smoking cessation

Adequate sleep duration ( a minimum of 6 hours/night) is also recommended. Short sleep duration (typically defined as < 5 or 6 hours per night in adults, has been associated with hypertension (5). For example, studies suggest that optimizing sleep quality and duration (> 6 hours/night) improves blood pressure control in patients with chronic kidney disease (6).

Dietary modifications can also help control diabetes, obesity, and dyslipidemia. Patients with uncomplicated hypertension do not need to restrict their activities as long as blood pressure is controlled.

(See also Medications for Hypertension.)

The decision to treat with medication is based on the BP level and the presence of atherosclerotic cardiovascular disease (ASCVD) or its risk factors (see table Initial Approach to Management of High Blood Pressure). The presence of diabetes or kidney disease is not factored in separately because these diseases are part of ASCVD risk assessment.

An important part of management is continued reassessment. If patients are not at goal BP, clinicians should strive to optimize adherence to the current regimen before switching or adding medications.

Treatment of  hypertension during pregnancy requires careful medication selection because some antihypertensive medications can harm the fetus.

Medication selection is based on several factors, including comorbidities, contraindications, and tolerability. For most patients, when selecting an agent for monotherapy, initial treatment may be with any of the following medication classes:

• Angiotensin-converting enzyme (ACE) inhibitor

• Angiotensin II receptor blocker (ARB)

• Dihydropyridine calcium channel blocker

• Thiazide diuretic (preferably a thiazide-like diuretic such as chlorthalidone or indapamide)

In addition, some experts recommend that for patients of African ancestry who are candidates for monotherapy, a calcium channel blocker or a thiazide diuretic should be used initially as these drugs are more effective for patients with low renin salt-sensitive hypertension (7, 8, 9, 10). However, there is substantial variability in blood pressure response within racial groups (11), and data suggest that despite use of this race-based approach, control of hypertension and racial disparities in blood pressure control have not improved (12). Thus, some experts favor an individualized approach to therapeutic selection rather than a race-based approach.

Most patients require ≥ 2 medications as treatment of hypertension often starts late in the course. When combination therapy with 2 antihypertensive agents is selected, options include either an ACE inhibitor or ARB combined with either a diuretic or a calcium channel blocker. Many combinations are available as single pills, which may improve patient adherence (13, 14).

Signs of hypertensive emergencies require immediate blood pressure reduction with parenteral antihypertensives. Such signs may include seizures or focal neurologic symptoms, retinal hemorrhage, chest pain, dyspnea,or nausea and vomiting.

Some antihypertensives are avoided in certain disorders (eg, ACE inhibitors in severe aortic stenosis) whereas others are preferred for certain disorders (eg, calcium channel blockers for patients with angina pectoris, ACE inhibitors or ARBs for patients with diabetes and proteinuria—see tables Initial Choice of Antihypertensive Medication Class and Antihypertensives for Patients With Comorbidities).

If the goal BP is not achieved within 1 month, assess adherence and tolerability and reinforce the importance of following treatment. If patients are adherent with the regimen, the dose of the initial medication can be increased or a second medication added (selected from among medications recommended for initial treatment). Note that an ACE inhibitor and an ARB should not be used together. Therapy is titrated frequently. If target BP cannot be achieved with 2 medications, a third medication from choices of initial medications is added. If such a third medication is not tolerated or is contraindicated, a medication from another class (eg, aldosterone antagonist) can be used. Patients with such difficult to control BP may benefit from consultation with a hypertension specialist.

If initial systolic BP is > 160 mm Hg, 2 medications should be initiated regardless of cardiovascular disease risk. An appropriate combination and dose are determined. For resistant hypertension (BP remains above goal despite use of 3 different antihypertensive medications), 4 or more medications are commonly needed.

Achieving adequate blood pressure control often requires several evaluations and changes in pharmacotherapy. Reluctance to titrate or add medications to control BP must be overcome. Nonadherence to therapy, particularly because lifelong treatment is required, can interfere with adequate BP control. Education, with empathy and support, is essential for success.

Renal artery sympathetic nerve ablation, using percutaneous catheter-based radiofrequency devices, should be considered experimental and used only in centers with extensive experience. Such devices are used in Europe and Australia for resistant hypertension. Several industry-funded sham-controlled studies with different patient populations (eg, untreated hypertension [15], treated hypertension [16], or resistant hypertension [17]) have demonstrated statistically and/or clinically significant reductions in systolic blood pressure. However, whether these devices reduce major cardiovascular events remains uncertain.

Baroreflex activation therapy has been proposed for management of resistant hypertension, but studies have not provided sufficient evidence to recommend the use of these devices (4). The therapy employs a battery-powered device surgically implanted around the carotid body to stimulate the baroreceptor and, in a dose-dependent manner, lower blood pressure. In one long-term follow-up study of patients with resistant hypertension who were included in earlier pivotal trials, baroreflex activation therapy maintained its efficacy for persistent reduction of office BP without major safety issues (18).

Resistant hypertension is defined as blood pressure that is not controlled to goal despite adherence to 3 suitably dosed antihypertensive medications of different classes (including a diuretic) and after white coat effect is excluded. Blood pressure that requires 4 drugs to achieve control is also considered controlled resistant hypertension. Use of a mineralocorticoid receptor antagonist can be beneficial in attaining goal blood pressure (19).

Secondary causes of hypertension must be excluded as part of the evaluation for resistant hypertension. Hyperaldosteronism or subclinical hypercortisolism has been identified in 15 to 20% of cases of resistant hypertension.

1. 1. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial. JAMA 315(24):2673-2682, 2016. doi:10.1001/jama.2016.7050

2. 2. White WB, Wakefield DB, Moscufo N, et al. Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY). Circulation 140(20):1626-1635, 2019. doi:10.1161/CIRCULATIONAHA.119.041603

3. 3. Gomadam P, Shah A, Qureshi W, et al. Blood pressure indices and cardiovascular disease mortality in persons with or without diabetes mellitus. J Hypertens 36(1):85-92, 2018. doi:10.1097/HJH.0000000000001509

4. 4. Table 15. Nonpharmacological Interventions. In: Whelton PK, Carey RM, Aronow WS, et al: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 71(6):e13–e115, 2018. doi: 10.1161/HYP.0000000000000065

5. 5. Thomas SJ, Calhoun D. Sleep, insomnia, and hypertension: current findings and future directions. J Am Soc Hypertens 11(2):122-129, 2017. doi:10.1016/j.jash.2016.11.008

6. 6. Ali W, Gao G, Bakris GL. Improved Sleep Quality Improves Blood Pressure Control among Patients with Chronic Kidney Disease: A Pilot Study. Am J Nephrol 51(3):249-254, 2020. doi:10.1159/000505895

7. 7. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents [published correction appears in N Engl J Med 1994 Jun 9;330(23):1689]. N Engl J Med 1993;328(13):914-921. doi:10.1056/NEJM199304013281303

8. 8. Yamal JM, Oparil S, Davis BR, et al. Stroke outcomes among participants randomized to chlorthalidone, amlodipine or lisinopril in ALLHAT.J Am Soc Hypertens 2014;8(11):808-819. doi:10.1016/j.jash.2014.08.003

9. 9. Wright JT Jr, Harris-Haywood S, Pressel S, et al. Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2008;168(2):207-217. doi:10.1001/archinternmed.2007.66

10. 10. Hall WD, Reed JW, Flack JM, Yunis C, Preisser J. Comparison of the efficacy of dihydropyridine calcium channel blockers in African American patients with hypertension. ISHIB Investigators Group. International Society on Hypertension in Blacks. Arch Intern Med 158(18):2029-2034, 1998. doi: 10.1001/archinte.158.18.2029

11. 11. Mokwe E, Ohmit SE, Nasser SA, et al. Determinants of blood pressure response to quinapril in black and white hypertensive patients: the Quinapril Titration Interval Management Evaluation trial. Hypertension 2004;43(6):1202-1207. doi:10.1161/01.HYP.0000127924.67353.86

12. 12. Egan BM, Li J, Sutherland SE, Rakotz MK, Wozniak GD. Hypertension Control in the United States 2009 to 2018: Factors Underlying Falling Control Rates During 2015 to 2018 Across Age- and Race-Ethnicity Groups. Hypertension 78(3):578-587, 2021. doi:10.1161/HYPERTENSIONAHA.120.16418

13. 13. Parati G, Kjeldsen S, Coca A, Cushman WC, Wang J. Adherence to Single-Pill Versus Free-Equivalent Combination Therapy in Hypertension: A Systematic Review and Meta-Analysis. Hypertension 77(2):692-705, 2021. doi:10.1161/HYPERTENSIONAHA.120.15781

14. 14. Williams B, Mancia G, Spiering W, et al. 2018 Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension [published correction appears in J Hypertens 2019 Feb;37(2):456]. J Hypertens 8;36(12):2284-2309, 2018. doi:10.1097/HJH.0000000000001961

15. 15. Böhm M, Kario K, Kandzari DE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet 395(10234):1444-1451, 2020. doi:10.1016/S0140-6736(20)30554-7

16. 16. Mahfoud F, Kandzari DE, Kario K, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial. Lancet 399(10333):1401-1410, 2022. doi:10.1016/S0140-6736(22)00455-X

17. 17. Bhatt DL, Vaduganathan M, Kandzari DE, et al. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial. Lancet 400(10361):1405-1416, 2022. doi:10.1016/S0140-6736(22)01787-1

18. 18. de Leeuw PW, Bisognano JD, Bakris GL, Nadim MK, Haller H, Kroon AA, DEBuT-T and Rheos Trial Investigators. Sustained reduction of blood pressure with baroreceptor activation therapy: Results of the 6-year open follow-up. Hypertension 69:836–843, 2017.

19. 19. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: Detection, evaluation, and management: A Scientific Statement From the American Heart Association. Hypertension 72:e53–e90, 2018. doi: 10.1161/HYP.0000000000000084

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