REFRACTORY HYPERTENSION

03-01-2014

Definition:

• Resistant hypertension defined as blood pressure that remains above goal in spite of concurrent use of three antihypertensive agents of different classes

the 2008 American Heart Association scientific statement

• Thus, patients whose blood pressure is controlled with four or more medications should be considered to have resistant hypertension.

• One of the three agents should be a diuretic

• All agents should be prescribed at optimal doses (ie, 50 percent or more of the maximum recommended antihypertensive dose)

• Although patients with resistant hypertension may have elevations in both systolic and diastolic pressures, isolated systolic hypertension is common

• Resistant hypertension is not synonymous with uncontrolled hypertension

• since resistant hypertension is not the only cause of uncontrolled hypertension.

• Other causes include inadequate treatment regimens and pseudoresistance

Refractory hypertension

• Some patients with resistant hypertension cannot be controlled, even with maximal medical therapy i.e.four or more drugs with complementary mechanisms given at maximal tolerated doses under the care of a hypertension specialist

• Such patients are referred to as having refractory hypertension

• Refractory hypertension was defined as the inability to achieve blood pressure control (to less than 140/90 mmHg) despite at least three visits to the hypertension clinic over six or more months

• Many authors suggested neurologic mechanisms (eg, sympathetic overactivity).

• But this contrasts with the conventional thinking that resistant hypertension is largely due to persistent hypervolemia

Terminologies

• Apparent resistant hypertension

• Pseudoresistant hypertension

• True resistant hypertension

Apparent resistant hypertension

• Patients have uncontrolled clinic blood pressure (ie, greater than or equal to 140/90 mmHg) despite being prescribed three or more antihypertensive medications, or require prescriptions of four or more drugs to control their blood pressure

Pseudoresistant hypertension

• Pseudo resistance refers to poorly controlled hypertension that appears resistant to treatment but is actually attributable to other factors

• The five most common causes of pseudoresistance are:

1. Inaccurate measurement of blood pressure2. Poor adherence to antihypertensive therapy3. Suboptimal antihypertensive therapy4. Poor adherence to lifestyle and dietary approaches 5. White coat hypertension

True resistant hypertension

• Patients with true resistant hypertension are those who have uncontrolled clinic blood pressure despite being compliant with an antihypertensive regimen that includes three or more drugs (including a diuretic, and each at optimal doses)

• and who also have uncontrolled blood pressure confirmed by 24-hour ambulatory blood pressure monitoring.

White coat hypertension

• Also called isolated clinic or office hypertension

• Refers to patients who have office readings that average more than 140/90 mmHg and reliable out of office readings that average less than 140/90 mmHg

• Having the BP in the office taken by a nurse or technician, rather than the physician, may minimize the white coat effect

Clue in diagnosis is……..

• Patients with white coat hypertension have less severe target organ damage and appear to be at less cardiovascular risk compared to those patients with persistent hypertension during ambulatory monitoring

PREVALENCE

• The true prevalence of resistant hypertension is not known

• A major problem is that not all patients with uncontrolled hypertension have resistant hypertension as defined above; many are uncontrolled because of poor adherence or inadequate treatment regimens

Risk factors

• Extracellular volume expansion — Relative or absolute volume expansion is frequently at least partially responsible for an inability to control hypertension BP

• Underlying renal insufficiency, sodium retention due to therapy with vasodilators, and/or ingestion of a high salt diet (which can be assessed by measuring sodium excretion in a 24-hour urine collection) all may play a role.

causes

• Patients with resistant hypertension are much more likely to have an identifiable cause of hypertension

• The most common are primary aldosteronism and renal artery stenosis, chronic kidney disease, and obstructive sleep apnea

• Less common causes include pheochromocytoma, Cushing's syndrome, and aortic coarctation

Primary aldosteronism

• Primary aldosteronism has been reported in approximately 10 to 20 percent of patients with resistant hypertension

• Otherwise unexplained hypokalemia is the major clue

Renal artery stenosis

• Renal artery stenosis is a common cause of resistant hypertension and can be due to either atherosclerotic disease or, in younger patients, fibromuscular dysplasia.

Chronic kidney disease

• As renal function declines there is an increasing need for additional antihypertensive medications

• Diuretics play a central role.

• Diuretics should be pushed until the blood pressure goal is reached or the patient has attained "dry weight" or decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the blood urea nitrogen and/or serum creatinine concentration

Obstructive sleep apnea

• Obstructive sleep apnea is common among patients with resistant hypertension who are referred for sleep studies

• screening to be done in patients with resistant hypertension who have one or more of the following risk factors: obesity, loud snoring, and/or daytime sleepiness

• The treatment of obstructive sleep apnea with positive airway pressure provides a usually modest antihypertensive benefit among patients with hypertension

• Medical history — The medical history should document age of onset, duration, severity, and progression of the hypertension

• Current medication use (including herbal and over-the-counter medications) and the response to prior medications should be determined. Patient adherence is established mostly by self-report

• The clinician should ask about adverse effects of medications, out-of-pocket costs, and dosing inconvenience, all of which can limit adherence.

• The patient should also be questioned about possible manifestations of secondary causes of hypertension, such as pheochromocytoma and Cushing's syndrome

• Physical examination — The physical examination should include careful measurement of the blood pressure and funduscopic examination looking for retinopathy

• In addition, signs that suggest secondary causes of hypertension may be present.

• As examples, carotid, abdominal, or femoral bruits suggest atherosclerotic diseaseand possible renal artery stenosis,

• Diminished femoral pulses and/or a discrepancy between arm and thigh blood pressures suggest aortic coarctation or significant aortoiliac disease

• serum electrolytes, glucose, and creatinine, and a urinalysis with estimation of proteinuria (eg, urine albumin-to creatinine ratio).

• Screening for primary aldosteronism begins with a paired, morning measurement of the plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to PAC/PRA ratio.

• In addition to blood testing, a 24-hour urine collection should be obtained on the patient's usual diet for determination of sodium excretion, creatinine clearance, and aldosterone excretion.

• Urinary sodium excretion permits estimation of dietary sodium intake unless the patient has been recently (within the past two weeks) started on a diuretic or there has been a recent dose increase

• Patients with resistant hypertension should be evaluated for pheochromocytoma if they have suggestive manifestations such as episodic hypertension, palpitations and/or diaphoresis, or tremor

• Noninvasive imaging — Most patients with resistant hypertension should undergo noninvasive imaging for renal artery stenosis

1.known atherosclerotic disease in other vascular beds,2.including peripheral artery disease3.coronary artery disease or 4.cerebrovascular disease,5.a rise in serum creatinine after initiation of ACEI or ARBS6.onset of hypertension at a young age which could represent fibromuscular dysplasia

• The choice of agents should be individualized and may depend upon consideration of prior benefit, history of adverse events, financial limitations, and the presence of concomitant disease processes such as chronic kidney disease or diabetes.

• The triple combination of an ACE inhibitor or ARB, a long-acting dihydropyridine calcium channel blocker (usually amlodipine), and a long-acting thiazide diuretic (preferably chlorthalidone) is often effective and generally well tolerated

Our approach varies with the patient's regimen:

• If the patient is on hydrochlorothiazide, we switch to chlorthalidone.

• If the current regimen includes a drug not from the three recommended drug classes, we add the missing preferred drug and assess the response. We do not discontinue any drugs, as long as they are well tolerated, before achieving blood pressure control.

• If the patient is still hypertensive despite being treated with the three preferred drugs, we add an aldosterone antagonist.

• If the patient is still hypertensive, additional medications are added sequentially.

Possible agents that may be used include:

• Beta blockers (labetalol, carvedilol, or nebivolol)• Centrally acting agents (clonidine or guanfacine)• Direct vasodilators (hydralazine or minoxidil)

• If beta blockers are used, a vasodilating beta blocker, such as labetalol, carvedilol or nebivolol, may provide more antihypertensive benefit with fewer side effects compared to traditional beta blockers, particularly when high doses are used

• Aliskiren, the only available direct renin inhibitor, is at least as effective as ARBs in reducing end target organ damage but has not been directly tested in resistant hypertension

• The ALLAY trial showed that aliskiren monotherapy was as effective as losartan in reducing LVMI, although the combination of both did not achieve a statistically significant further LVMI regression

• Endothelin receptor antagonists are a new family of antihypertensive medications that are currently being evaluated.

• Darusentan is a selective antagonist for type A endothelin receptors, activation of which causes vasoconstriction and proliferation of vascular smooth muscle

• It has demonstrated significant dose-dependant reductions in both systolic and diastolic blood pressures and has been positively evaluated in resistant hypertension

• Atrasentan is another highly selective endothelin receptor antagonist that has shown positive results in blood pressure reduction for 72 patients

• Interestingly, it also had a positive influence on the patients metabolic profile

• Omapatrilat is such an agent that has been evaluated favorably in the OCTAVE trial

•  Another promising category under development is medication that combines inhibitors of vasoconstrictive mediators with drugs that potentiate vasodilating mediators by inhibiting their breakdown by neutral endopeptidases (NEPs)

EXPERIMENTAL THERAPIES

1. Radiofrequency ablation of renal sympathetic nerves

2. Stimulation of carotid sinus baroreceptors

radiofrequency ablation of the renal sympathetic nerves should be reserved for patients who meet all of the following criteria :

• Resistant hypertension is present • Pseudoresistant hypertension has been excluded (eg, white coat

effect, medication nonadherence). • Identifiable secondary causes of resistant hypertension, such as

primary aldosteronism, have been excluded.• Renal function is preserved (estimated glomerular filtration rate

greater than or equal to 45 mL/min/1.73 m ).• The renal artery anatomy is eligible (ie, there are no accessory renal

arteries and no renal artery stenosis or renal artery revascularization)

Baroreceptor mechanism