Challenges in Managing Resistant Arterial Hypertension

In 2007, the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines define AH as systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg, based on at least 2 readings obtained in at least 2 occasions. This is stricter than the 2003 guidelines from the Seventh Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure , which defined AH as blood pressure ≥140/90 mm Hg. As a result of the new definition, the prevalence of HA in the US increased from nearly 32% to 47%. AH is one of the main causes of cardiovascular diseases and death.

Target blood pressure should be individualized based on patient characteristics, medication adverse effects, tolerance, and preferences.

In patients with cardiovascular disease or risk of an atherosclerotic cardiovascular disease event ≥10% in the next 10 years, the 2017 ACC-AHA guidelines recommend “a target blood pressure <130/80 mm Hg.”

In lower-risk patients, the ACC-AHA guidelines say the same goal “may be reasonable.”

In patients with chronic kidney disease, the 2021 Kidney Disease Improving Global Outcomes guideline recommended agreeing on a systolic blood pressure value <120 mm Hg depending on the appropriateness of the measurement. This recommendation is based largely on the benefits of this lower target on the cardiovascular system, as demonstrated by the Systolic Blood Pressure Intervention Trial , in which nondiabetic patients at risk for cardiovascular disease were randomly assigned to achieve blood pressures. arterial <120 mm Hg or <140 mm Hg.

In a subgroup analysis of chronic kidney disease, the intensive group had a slightly higher rate of change in estimated glomerular filtration rate (−0.47 vs. −0.32 ml/min/1.73 m2/year) after 6 months. The decline in renal function may be hemodynamically mediated as a result of more intensive blood pressure control.

In patients with diabetes , the American Diabetes Association recommends a blood pressure goal of <130/80 mm Hg. Most people do not achieve these goals. In the US, only 20.6% of hypertensives have their blood pressure controlled using the 2017 ACC-AHA definitions. The control rate was 62.8% using the old threshold of <140/90 mmHg.

Resistant arterial hypertension (HR) is defined by ACCAHA as blood pressure that is above the target despite the patient receiving at least 3 medications with different mechanisms of action.

All medications should be prescribed at maximum tolerated doses and preferably include a long-acting calcium channel blocker, dihydropyridine, either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB). and a diuretic. HR is also defined as blood pressure controlled with at least 4 antihypertensive medications.

Pseudo resistance is suboptimal blood pressure control secondary to medication nonadherence, white coat effect, or poor measurement technique.

HA apparently refractory to treatment (HAART) is the term used in epidemiological studies to refer to patients who meet HR criteria but have not verified medication compliance or dosing, or have not had blood pressure records. outside the office to rule out the white coat effect.

The prevalence of RH is difficult to determine precisely due to the need to rule out pseudo resistance. However, based on data from a major survey, the prevalence of HAART (using the cutoff of ≥140/90 mm Hg) in the general public is estimated to be 12.8%. On the other hand, a cohort study of hypertensive patients with chronic renal failure found a HAART prevalence of 40.4%, using the same definition.

Other comorbidities associated with RH include advanced age, obesity, diabetes mellitus, and obstructive sleep apnea.

Of the 116 million Americans with hypertension, only 20.6% have their blood pressure controlled using the ACC-AHA 2017 definition .

RH is associated with worse outcomes, particularly adverse renal outcomes, cardiovascular morbidity, and death. In a study of 10,001 patients, HAART was associated with a 64% higher incidence of a composite of adverse cardiovascular outcomes due to fatal coronary heart disease, nonfatal myocardial infarction, cardiac arrest, and stroke. HAART has been shown to increase the risk of kidney failure.

The diagnosis of HR requires ruling out pseudo- resistance due to lack of adherence to medication, inadequate blood pressure measurement, and the white coat effect.

> Is the patient taking the medication?

Medication nonadherence is a discrepancy between how a medication is prescribed and how the patient is actually taking it. Its prevalence in patients on HAART is difficult to determine. Studies have shown it to range from 3% to 86%, with a pooled estimate of 31% in a meta-analysis.

Medication adherence can also be difficult to achieve, but several techniques have been studied. Some laboratories offer serum and urine analysis to detect metabolites of antihypertensive drugs and pharmaceutical evaluations that include pharmacy dispensing history and pill counts. It has been shown that direct observation of treatment reduces HR by 29%. Each of these methods has limitations such as inaccuracies in patient reports and physician interviews, as well as the impracticality and cost of directly observing therapy or measuring drug metabolites.

It is important to ensure that patients understand their medication instructions and share decisions, in order to improve adherence.

> Are the measurements accurate?

Accurately measuring blood pressure requires proper technique, proper cuff size, and use of validated devices.

For office use, automated monitoring is preferable to conventional manual auscultation devices. These devices are designed to take multiple blood pressure readings in a single session. In one study, mean systolic blood pressure taken in the office by automated devices was 11 mm Hg lower than those obtained with manual devices. Results from in-office automated devices were more consistent with those obtained with ambulatory blood pressure monitoring.

Sources of inaccuracy of auscultatory blood pressure measurement include: inadequate operator skill, inability to hear Korotkoff sounds, and terminal digit bias. If blood pressure is measured using the auscultatory technique, close attention should be paid to operator training, appropriate cuff size, and technique. Aneroid sphygmomanometers require more frequent calibration than oscillatory devices.

To monitor BP and complement in-office records and not as the only measurement, current guidelines recommend measuring blood pressure outside of the office.

This may improve blood pressure diagnosis and help detect other forms of HA such as white coat or masked HA.

2 monitoring methods are used: self-measurement and ambulatory monitoring.

• Self -measurement means that the patient takes their blood pressure at regular times during the day. While there is no consensus on the optimal schedule for monitoring blood pressure at home, measurements 2 to 3 times consecutively can be performed 2 times/day, in the morning and afternoon, for a minimum of 3. Ideally 5 to 7 consecutive days per month. The authors recommend measuring blood pressure before taking antihypertensive medications to better assess control.
   
• Ambulatory monitoring records blood pressure over a 24-hour period. An advantage is its ability to measure nighttime blood pressure. Blood pressure normally decreases by 10% to 20% during sleep, and “no-dippers” have a 10-20% reduction in nighttime blood pressure. increased risk of suffering cardiovascular events.

White-coat BP appears in office measurements in people who are not on antihypertensive treatment and who have normal blood pressures outside the office.

In contrast, the white coat effect is the same pattern in a person who is receiving treatment for hypertension. This effect can be seen in 28% to 39% of those with HR. Untreated white coat HA is associated with increased risk of cardiovascular events compared to sustained normotension.

In a recent meta-analysis, patients with white coat effect (i.e., during treatment, with normal blood pressures at home but elevated in the office) showed no increased cardiovascular risk compared with those with controlled HA. Masked BP is blood pressure that is normal in office readings but elevated outside the office.

People with masked AH are at greater risk of cardiovascular events than normotensive patients or those with white-coat AH.

> Does the patient have lifestyle factors that elevate blood pressure?

Obesity

The relationship between increased adiposity and high blood pressure has been well established.

In the NHANES study, participants with a body mass index ≥30 kg/m2 were twice as likely to have HR or HAART. The pathogenic mechanisms of obesity-related AH include increased salt sensitivity, increased activity of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system, and secretion of aldosterone by adipose tissue. Of these mechanisms, aldosterone secretion by adipose tissue is the only one specific to obesity, since the others can also occur in diseases such as chronic kidney disease and heart failure.

In NHANES hypertensive adults, ACEIs and ARBs had a more pronounced antihypertensive effect in obese women than in nonobese women. This effect was not observed in men. However, so far there are no guidelines to recommend specific blood pressure medications for patients with obesity vs. not obesity.

> Amount of sodium in the diet.

Sodium in the diet increases blood pressure.

This effect may not occur in all people, but it may occur in certain groups more sensitive to salt, including older adults, black people, and patients with chronic kidney disease. In a randomized crossover trial of 12 patients with RH, reducing dietary sodium from 5750 mg/day to 1150 mg/day for 1 week reduced office systolic pressure by 22.7 mm Hg.

HR patients had a more significant reduction in blood pressure than other HA patients or the general population, suggesting that salt sensitivity may play a more important role in the pathogenesis of resistant HA and reinforcing the importance of including a diuretic in the treatment plan.

Patients should be advised to follow a diet with less than 2 g sodium/day (5 g table salt) in addition to the low-sodium DASH (Dietary Approaches to Stop Hypertension). and rich in fruits, vegetables and low-fat dairy products, since the combination of these 2 was shown to be more effective than either of the 2 alone.

> Recommended exercise

Aerobic exercise has been shown to reduce blood pressure in patients with AH and RH. Patients with HR who enrolled in a treadmill exercise program for 8 to 12 weeks reduced their daytime systolic pressure by 5.9 mm Hg (±11.6 mm Hg). In another study, those who exercised for 60 minutes in a heated pool 3 times/week for 2 weeks experienced a reduction in ambulatory systolic blood pressure of 12 mm Hg in 24 hours and a reduction of 9 mm Hg in diastolic blood pressure .

Patients should participate in at least 150 minutes per week of moderate-intensity aerobic exercise or 75 minutes per week of vigorous aerobic activity. Both isometric exercise and dynamic resistance exercise have been shown to reduce blood pressure, presenting other options for patients with limited mobility who cannot do aerobic exercise.

> Alcohol consumption

Regular alcohol consumption has been shown to increase blood pressure by 1 mm Hg for every 10 g of alcohol consumed (approximately 1 standard drink), an effect that is reversible within a few weeks of cessation.

> Smoking, chewing, vaping

Nicotine , most commonly found in cigarettes, vaping liquid, and smokeless tobacco, causes an increase in blood pressure . Treatment interruption should be recommended to all patients in general and especially to those with HR in order to improve their already increased risk of cardiovascular events. Nonsteroidal anti-inflammatory drugs, at any dose high enough to relieve pain, can increase blood pressure by 2 to 5 mm Hg.

Medications that can raise blood pressure are:

• Nonsteroidal anti-inflammatory drugs, including cyclooxygenase 2 inhibitors. These drugs are ubiquitous and can increase blood pressure at any dose high enough to relieve pain, 2 to 5 mm Hg. Importantly, low-dose aspirin is not associated with HA

• Glucocorticoids

• Serotonin and norepinephrine reuptake inhibitors

• Estrogen-containing contraceptives and other estrogen-containing medications

The effects of these medications on blood pressure are usually reversible after discontinuation.

•Sympathomimetics (pseudoephedrine, ephedrine, cocaine, amphetamine)

• Vascular endothelial growth factor inhibitors 

• Erythropoietin stimulating agents 

• Calcineurin inhibitors (cyclosporine, tacrolimus); Elevation of blood pressure with calcineurin inhibitors is usually treated with calcium channel blockers.

• Tyrosine kinase inhibitors

• Dietary supplements, including ginseng and licorice. The intensity of the effect of these medications on blood pressure can vary greatly from person to person.

Patients with RH should be evaluated for the presence of secondary AH, and recognition and targeted therapy may improve blood pressure control.

> Renal parenchymal disease

AH is both a cause and consequence of chronic kidney disease and is common in this patient population. A cohort study of patients with chronic kidney disease showed that 85.7% had a diagnosis of AH at their initial visit. In less than half (46.1%) the blood pressure was <130/80 mm Hg.

Proposed mechanisms of HA in kidney disease include upregulation of the renin-angiotensin-aldosterone system, increased salt and fluid retention, endothelial dysfunction, and increased activity of the sympathetic nervous system. Kidney disease should be evaluated and considered as a risk factor for HR in patients with elevated serum creatinine or an abnormal urinalysis.

> Primary aldosteronism

Primary aldosteronism ( or hyperaldosteronism) is due to autonomous hypersecretion of aldosterone. Excess circulating aldosterone causes salt and water retention and renal potassium loss, resulting in AH and cardiovascular disease. Primary aldosteronism is more common than previously thought and often goes undiagnosed. Its prevalence is 8% and 30% in various HA populations.

Hypokalemia, as a result of renal loss of potassium, is only seen in 9% to 37% of patients. patients who have primary aldosteronism, so this disease can go unnoticed.

Measurement of the ratio of aldosterone to renin in plasma is the most widely used test to detect primary aldosteronism. However, this test has the potential for false-positive and false-negative results, depending on whether patients are taking medications that interfere with the renin-angiotensin-aldosterone system, the cutoff values ​​used, the timing of the test, and the position of the test. body at the time of the test (preferably in the morning, after sitting for 15 minutes).

The Endocrine Society guidelines recommend initial testing of the aldosterone-renin ratio followed by confirmatory testing (intravenous or oral salt loading test) for patients with AH and at risk for primary aldosteronism. Patients at risk are those with HR on optimal therapy, spontaneous or diuretic-induced HA, hypokalemia, and HA due to adrenal incidentaloma, as well as first-degree familial HA in patients with primary aldosteronism.

An aldosterone-renin ratio ≥20 or should warrant further investigation if the plasma aldosterone concentration is ≥15 ng/dl. Patients with very low renin levels, spontaneous hypokalemia, and plasma aldosterone concentration >20 ng/dl probably do not require confirmatory testing; The study should be completed with adrenal imaging.

Primary aldosteronism due to a unilateral aldosterone-secreting adrenal adenoma is treated with surgery or with mineralocorticoid receptor antagonists, such as spironolactone. In bilateral adrenal disease and in patients who are not candidates for surgery, the indication is eplerenone. Screening and diagnosis according to current guidelines can detect only a fraction of patients with primary aldosteronism, so new practice guidelines are necessary.

> Obstructive sleep apnea

Obstructive sleep apnea is very common in patients with resistant hypertension (RH).

Proposed mechanisms by which this apnea could cause or worsen AH include increased upper airway resistance, hypoxia, and hypercapnia. These cause endothelial reactivity, inflammation, oxidative stress and increase in the sympathetic system and the renin-angiotensin-aldosterone system which, ultimately, in AH leads to an increase in vascular tone.

It has been shown that with the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP), 24-hour ambulatory AH decreases. The more hours per night CPAP is used, the greater the effect on blood pressure. However, although treatment of obstructive sleep apnea with CPAP is recommended to reduce the risk of other cardiovascular complications, a meta-analysis found only a modest 2.46 mm Hg reduction in systolic blood pressure.

Obesity and obstructive sleep apnea are risk factors for HR, but a study that analyzed the effect of CPAP therapy on blood pressure in patients with obesity vs. those without obesity did not find significant differences between the groups. Given the high prevalence of obstructive sleep apnea in people with HR, common screening is warranted in this patient population. Screening tools such as the STOP BANG score can help risk stratify patients with suggestive symptoms and which of them should undergo polysomnography, which is the gold standard for diagnosis.

The STOP-BANG score consists of 8 factors that spell the acronym: snoring, tiredness or drowsiness during the day, stops breathing during sleep, HA, body mass index >35 kg/m2, age >50 years, neck circumference ≥43 cm in men or ≥40 cm in women, and male gender. If ≥3 factors are present, the patient is at high risk for obstructive sleep apnea.

Renovascular HA is a syndrome with elevated blood pressure due to decreased renal artery blood flow causing renal ischemia.

The most common cause is atherosclerosis of the renal arteries but other pathological processes include fibromuscular dysplasia, renal artery infarction or dissection, and vasculitis.

Diagnosis of renal artery stenosis includes imaging with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography. At least 70% of the renal artery must be stenosed before the lesion can be considered the cause of AH. Atherosclerotic renovascular disease is considered to be an equivalent of coronary artery disease and its treatment consists of medical management focused on blood pressure, lipid and glucose control, and antiplatelet therapy.

Percutaneous revascularization should generally be considered in patients with the following high-risk characteristics:

• Recurrent heart failure or sudden unexplained pulmonary edema.

• HR with failure of optimal medical management.

• Rapid decrease in glomerular filtration rate, unexplained

• Bilateral renal artery stenosis or single functioning kidney, with stenosis associated with any of the above.

Catecholamine-secreting tumors, such as pheochromocytomas and paragangliomas, are rare causes of HA in 0.2% to 0.6% of cases, but are associated with a significant risk of mortality.

Symptoms that should prompt screening include paroxysmal headache, diaphoresis, and tachycardia. The 2014 Endocrine Society guidelines recommend screening by measuring free metanephrines in plasma or fractionated metanephrines in 24-hour urine.

Patients having plasma metanephrines measured should remain supine for at least 30 minutes before sampling. Normetanephrine and metanephrine levels ≥3 times higher than the upper limit of normal are highly suggestive of a catecholamine-producing tumor.

Medications that can cause elevated levels of metanephrines and catecholamines include tricyclic antidepressants, amphetamines, monoamine oxidase inhibitors, and levodopa. Withdrawal from clonidine can have the same effect.

Cushing’s disease or syndrome (hypercortisolism due to excess glucocorticoids) is a relatively rare disease that causes RH. Cushing’s syndrome is a constellation of symptoms that classically includes glucose intolerance, acne, osteoporosis, obesity, menstrual disorders, hirsutism, muscle atrophy, and moon facies.

Interestingly, the authors say, in one study, 26.5% of patients with RH but without obvious symptoms or signs of Cushing’s syndrome had biochemical evidence of hypercortisolism, suggesting that doctors should consider testing for it. in patients without the classic syndrome. Patients should be screened by measuring 24-hour urinary cortisol level or late-night salivary cortisol level, or a low-dose dexamethasone suppression test.

Less common endocrine disorders that may contribute to RH include disorders of the thyroid and parathyroid glands. Thyroid-stimulating hormone levels should be monitored in people with difficult-to-control HA. Testing for primary hyperparathyroidism should be considered in any patient who presents with hypercalcemia.

All patients diagnosed with RH should be screened for causes of secondary HA, based on the individual’s history, physical findings, and risk factors.

A multifactorial approach to treating RH includes a combination of lifestyle, pharmacotherapy, and addressing the underlying contributing diseases. Patients with RH should be screened for end-organ damage (e.g., serum) creatinine and urinalysis to look for kidney disease, electrocardiography or echocardiography to evaluate for left ventricular hypertrophy, and an ophthalmologic examination to detect possible retinopathy. hypertensive.

The prescription of antihypertensive treatment begins with the identification of comorbidities that require the attention of first-line agents that have a compelling indication, such as β-blockers for heart failure, history of myocardial infarction or aortic dissection, or medications that block the renin system. -angiotensin-aldosterone for proteinuria.

The initial pharmacological approach to RH consists of 3 medications, each with different mechanisms of action, in the maximum tolerated doses, as follows:

• An ACEI or an ARB (ARBs may be better tolerated than ACEIs, as they do not have the same risk of angioedema or cough. For the start of treatment, some experts prefer them to ACEIs).

• A long-acting dihydropyridine-type calcium channel blocker.

• A diuretic.

In patients with a preserved glomerular filtration rate, the preferred first-line diuretic is chlorthalidone or indapamide due to their longer half-life and more potent antihypertensive effect compared to hydrochlorothiazide. Loop diuretics are preferred in patients with an estimated glomerular filtration rate <30 ml/min/1.73 m2. Torsemide can be used once/day, but shorter-acting loop diuretics, such as furosemide or bumetanide, should be dosed at least twice/day. A recent randomized controlled trial demonstrated that chlorthalidone was effective in those with an estimated glomerular filtration rate of 15 to 30 mL/min/1.73 m2, thus representing another agent available for this population.

If blood pressure is not yet controlled with maximally tolerated therapy with these 3 agents, a mineralocorticoid receptor antagonist (spironolactone or eplerenone) should be the fourth-line agent.

The PATHWAY-2 trial demonstrated that spironolactone was superior in reducing blood pressure compared to bisoprolol (a β-blocker), doxazosin (a blocker), or placebo as adjunctive therapy in patients with HR on 3 antihypertensive medications. Side effects of spironolactone include hyperkalemia and gynecomastia.

The drug should be used with caution in chronic kidney disease. If gynecomastia becomes intolerable, spironolactone can be replaced by eplerenone, a selective aldosterone receptor antagonist that has minimal interaction with the steroid receptors of sex hormones. However, spironolactone is preferred because it has been extensively studied, is less expensive, and requires only once-daily intake due to a longer half-life compared to eplerenone.

The addition of other agents should be based on individual factors. Vasodilatory β-blockers (labetalol, carvedilol, nebivolol, bisoprolol) may be preferred as fifth-line agents. Other options include clonidine, a centrally acting α-2 agonist. Clonidine can be administered as a transdermal patch to improve adherence, minimize frequent oral dosing, and reduce the risk of rebound HA. According to AHA guidelines, if the target blood pressure has not yet been achieved, hydralazine may be prescribed, with an initial dose of 25 mg, 3 times/day.

In the presence of heart failure with reduced ejection fraction, a nitrate will be added. Finally, if hydralazine is not tolerated, minoxidil can be used. Hydralazine and minoxidil are associated with fluid retention and reflex tachycardia. Recent studies have shown that aldosterone synthase inhibitors and dual endothelin antagonists may be effective for HR. Although the US FDA has not approved either of these two medications for this indication, these agents may represent an optional additional treatment after further study.