D.BASEM ELSAID ENANYLECTURER OF CARDIOLOGY

AINSHAMS UNIVERSITY

Resistant Hypertension: Treatment

Resistant hypertension

--Definition:2008 American Heart Association guideline blood pressure that remains above goal in spite of concurrent use of three antihypertensive agents of different classes, one of which should be a diuretic. Patients whose blood pressure is controlled with four or more medications are considered to have resistant hypertension (20-30%).

Treatment of resistant hypertension

1-Identify and treat secondary hypertension.2-Stop medications that raise the blood pressure (next slide).3-Out-of-office BP monitoring:Apparently resistant patients should be evaluated by out-of office blood pressure measurements, either by self measurement of blood pressure at home or by ambulatory monitoring. Both home and ambulatory blood pressure measurements help to identify white coat hypertension.4-NONPHARMACOLOGIC THERAPY5-PHARMACOLOGIC THERAPY

- Nonnarcotic analgesics- Nonsteroidal antiinflammatory agents, including aspirin- Selective COX-2 inhibitors- Sympathomimetic agents (decongestants, diet pills, cocaine)- Stimulants (methylphenidate, dexmethylphenidate, dextroamphetamine, amphetamine, methamphetamine,modafinil)- Alcohol- Oral contraceptives- Cyclosporine- Erythropoietin- Natural licorice- Herbal compounds (ephedra or ma huang)

Diuretics

--Persistent volume expansion (typically not sufficient to produce edema) contributes to resistant hypertension, even among patients who have been on conventional doses of thiazide diuretics. Serum brain-type natriuretic peptide and atrial natriuretic peptide levels are significantly higher, suggesting volume expansion.--Diuretics should be titrated until the blood pressure goal or the maximum recommended dose has been reached or the patient has signs suggestive of overdiuresis such as fatigue, orthostatic hypotension, or decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the serum creatinine concentration.--In those with little renal impairment, chlorthalidone is preferred to hydrochlorothiazide for the treatment of resistant hypertension.--Begin chlorthalidone at 12.5 mg daily, which requires splitting of the 25 mg pill, with subsequent titration up to 25 mg daily or, rarely, higher. {serum K}

--Among patients with an estimated glomerular filtration rate of less than 30 mL/min per m2, thiazide diuretics are less effective and loop diuretics, such as furosemide, torsemide, or bumetanide, may be necessary for effective volume control. Furosemide is relatively short acting and usually requires at least twice daily dosing. A loop diuretic with a longer duration of action and more consistent absorption, such as torsemide, may be more effective

Aldosterone antagonists

--Spironolactone, eplerenone, and amiloride provide significant antihypertensive benefit when added to existing multiple drug regimens in patients with resistant hypertension .{significantly higher plasma aldosterone levels in patients with resistant hypertension compared with individuals who have normal blood pressure or controlled hypertension }--Spironolactone may be more likely to cause hyperkalemia in patients with chronic kidney disease .

CHOICE OF REGIMEN

--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. --Uncontrolled with such a three drug regimen at maximum recommended and tolerated doses spironolactone: 12.5 mg/day (which requires splitting of a 25 mg tablet) before titrating to 25 and, if necessary, 50 mg/day. The risk of adverse effects such as gynecomastia, breast tenderness, and erectile dysfunction increases with higher doses. [eplerenone, is now generic and does not induce the side effects seen with spironolactone]

--Some patients with resistant hypertension are being treated with a three drug regimen different:If the patient is on hydrochlorothiazide, switch to chlorthalidone.If the current regimen includes a drug not from the three recommended drug classes, add the missing preferred drug and assess the response. Do not discontinue any drugs, as long as they are well tolerated, before achieving blood pressure control.

--If the patient is still hypertensive, additional medications are added sequentially. Possible agents that may be used include vasodilating beta blockers (labetalol, carvedilol, or nebivolol), centrally acting agents (clonidine or guanfacine)[may be effective, but adverse effects are common], and direct vasodilators (hydralazine or minoxidil) [Fluid retention and tachycardia are common side effects. Minoxidil also causes hirsutism, which may be a particular problem in women that may require switching to hydralazine(lupus like=withdrawal, nausea, vomiting, flushing,tachycardia), and pericarditis].

Catheter-based radiofrequency ablation of renal sympathetic nerves

The mechanism by which renal sympathetic denervation improves management of BP is complex and involves the following factors:-Decreasing efferent sympathetic signaling to kidneys -Reducing norepinephrine spillover-Natriuresis-Increasing renal blood flow -Lowering plasma rennin activity-Decreasing renal afferent signalling and central sympathetic activation

Indications

--Refractory hypertension with office SBP >160 mmHg despite treatment with the least 3 antihypertensive medications including diuretic in optimal doses.--Exclusion of secondary forms of hypertension. --Exclusion of “white coat” hypertension using ambulatory blood pressure monitoring.

SYMPLICITY HTN-3: Renal Denervation Fails to Reduce BP in Resistant-Hypertension Patients

Led by Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA) and Dr George Bakris (University of Chicago, IL), SYMPLICITY HTN-3 is a randomized, sham-controlled renal-denervation study in 535 patients with severe resistant hypertension. After six months, the mean change in systolic blood pressure was a reduction of 14.13 mm Hg in the renal-denervation arm and 11.74 mm Hg in the sham-controlled arm, a difference of 2.39 mm Hg that was not statistically significant.Regarding the change in the 24-hour ambulatory systolic blood pressure, the reduction at six months was 6.75 mm Hg in the renal-denervation arm and 4.79 mm Hg in the control arm, a difference of 1.96 mm Hg that was also not statistically 

Contraindications

--Increased bleeding risk (bleeding diathesis, thrombocytopenia, severe anemia) --Chronic renal disease --eGFR < 45 mL/min/1.73m2--Type 1 diabetes--Previous renal artery intervention (angioplasty, stent implantation)--Anatomic abnormalities and variants of renal artery including aneurysms, severe stenosis, reference diameter <4 mm, excessive tortuosity, aortic aneurysm --Age < 18 years--Pregnancy

Technique

--Vascular access is similar to renal angiography and angioplasty. --Current 5F system uses 6F guide catheters. After engaging the renal artery, and angiography to evaluate the anatomy of the renal arteries, the ablation catheter is placed under fluoroscopic guidance in the distal segment of the renal artery. --Each RF application is followed by retraction by at least 5 mm and rotation by 90 degrees of the catheter tip, from the first distal main renal artery bifurcation to the ostium. --To achieve complete denervation, multiple (4-6) RF applications are used depending on the length of the trunk of both renal arteries. This approach provides circumferential disruption of sympathetic nerves. --The procedure is performed under analgetic or conscious sedation to lessen the pain

Symplicity Catheter System Design (Medtronic Vascular)

**Procedure-related complications are:-Access site complication (hematoma, pseudoaneurysm, dissection)-Renal artery dissection-Progression of a pre-existing renal artery stenosis -Regeneration of efferent nerves leading to relapse of resistant hypertension-Bradycardia

--Was tested in the Symplicity-HTN-2 trial of 106 patients with resistant hypertension despite treatment with an average of five antihypertensive medications including a diuretic. --The patients were randomly assigned to renal sympathetic denervation or maintenance of previous medical therapy. --At six months, radiofrequency ablation significantly decreased the office blood pressure from 178/97 to 143/85 mmHg compared with no decrease in blood pressure in patients maintained on baseline antihypertensive therapy. --In addition, a systolic pressure of less than 140 mmHg was attained significantly more often with radiofrequency ablation (39 versus 6 %). --There was no significant difference between the groups in kidney function. Complications related to radiofrequency ablation included one femoral artery pseudoaneurysm.--Long-term data regarding efficacy and safety of radiofrequency ablation remain limited.

Possible indications

1-Sleep apnea:The mechanism of such effect of renal denervation of sleep apnea is unknown, however the influence on sodium retention and volemic status is likely to be involved.2-Insulin Resistance/type 2 diabetes mellitus:The beneficial effects on glucose metabolism may be explained by several effects of renal denervation: inhibition of central sympathetic tone, reduced release of norepinephrine, better perfusion of skeletal muscles mediated via a decrease of alpha-adrenergic tone leading to increased glucose uptake.3-Congestive Heart Failure:Increased sympathetic activity is present in patients with heart failure and it is correlated with functional class.

Electrical stimulation of carotid sinus baroreceptors

--Electrical stimulation of the carotid sinus baroreflex system, or baroreflex activation therapy (BAT), may decrease blood pressure in patients with resistant hypertension.--Three feasibility studies have shown reductions in blood pressure after implantation of a device designed to stimulate the carotid baroreflex system .

*In the Rheos Pivotal Trial, 265 patients with resistant hypertension underwent surgical implantation of a device designed to stimulate the carotid baroreceptors. One month after surgery, patients were randomly assigned to have BAT turned on immediately or to have BAT turned on six months later. The patients were followed for at least 12 months:--At six months, patients receiving BAT had a nonsignificantly larger decrease in systolic pressure (16 versus 9 mmHg) and a nonsignificantly greater likelihood of having a 10 mmHg or larger decrease in systolic pressure (54 versus 46 %). In addition, patients receiving BAT were significantly more likely to achieve a goal systolic pressure of 140 mmHg or lower (42 versus 24 %).--At twelve months, the mean reduction in systolic pressure in the BAT group was 25 mmHg; more than 80 % of these patients had at least a 10 mmHg decrease in systolic pressure.--Within one month of surgery, 35 % of patients had a serious procedure-related adverse event, including nerve injury. In most patients, procedure-related adverse events resolved spontaneously. Seven patients died (3 %), but none were attributable to the device.

*Malignant hypertension:--Refers to marked hypertension with retinal hemorrhages, exudates, or papilledema. These findings may be associated with hypertensive encephalopathy{cerebral oedema}. --Usually associated with BP>180/120 mmHg. However, it can occur at diastolic pressures as low as 100 mmHg in previously normotensive patients with acute hypertension due to preeclampsia or acute glomerulonephritis.

*Hypertensive urgency:--Severe hypertension (as defined by a diastolic blood pressure above 120 mmHg) in asymptomatic patients.--There is no proven benefit from rapid reduction in BP in asymptomatic patients who have no evidence of acute end-organ damage and are at little short-term risk.

Hypertensive urgencies

*BP>180/120mmHg, no symptoms apart from headache.*A relatively rapid reduction in blood pressure (BP) was recommended in the past. However, in the absence of symptoms a more gradual reduction in pressure is suggested.*While a variety of oral therapeutic modalities have been used, including clonidine, sublingual nifedipine, and oral or sublingual captopril, sublingual nifedipine is now contraindicated in this setting {blood pressure falls below the range at which tissue perfusion can be maintained by autoregulation}.

*All patients should be provided a quiet room to rest; this can lead to a fall in BP of 10 to 20 mmHg or more.*Previously treated hypertension:--Increase the dose of existing antihypertensive medications, or add another agent.--Reinstitution of medications in non-adherent patients.--Addition of a diuretic, and reinforcement of dietary sodium restriction, in patients who have worsening hypertension due to high sodium intake.*Rapidly lowering blood pressure below the autoregulatory range of an organ system (most importantly the cerebral, renal, or coronary beds) can result in reduced perfusion, leading to ischemia and infarction. It is usuallyappropriate in these situations instead to gradually reduce blood pressure over 24 to 48 hours.Most patients with hypertensive urgency can be treated as outpatients.

*Untreated hypertension:--The approach should take into consideration the individual patient's risk with persistence of severe hypertension, the likely duration of severe hypertension, and of cerebrovascular or myocardial ischemia with rapid reduction in blood pressure.--Relatively rapid initial blood pressure reduction (over several hours): oral furosemide (if the patient is not volume depleted) at a dose of 20 mg (or higher if the renal function is not normal); a small dose of oral clonidine (0.2 mg); or a small dose of oral captopril (6.25 or 12.5 mg) observed for a few hours, to ascertain a reduction in blood pressure of 20 to 30 mmHg longer acting agent is prescribed and the patient is sent home to follow up within a few days.--Reduction over one to two days: Depending on the patient, a calcium channel blocker (but not sublingual nifedipine), beta blocker or angiotensin converting enzyme (ACE) inhibitor or receptor blocker can be started. Examples in these categories are oral nifedipine 30 mg once daily (of the long-acting preparation), oral metoprolol XL 50 mg daily, or ramipril 10 mg once daily. Some experts initiate therapy with two agents or a combination agent, one of which is a thiazide diuretic. The rationale is that most patients with blood pressure ≥20/10 mmHg above goal.--Patients at high risk for cardiovascular events (eg, long-standing diabetes, known coronary artery disease or prior stroke), should probably be admitted.

MECHANISMS OF VASCULAR INJURY

--With mild to moderate elevations in blood pressure, the initial response is arterial and arteriolar vasoconstriction. This autoregulatory process both maintains tissue perfusion at a relatively constant level and prevents the increase in pressure from being transmitted to the smaller, more distal vessels.

--With increasingly severe hypertension, however, autoregulation eventually fails damage to the vascular wall. Disruption of the vascular endothelium then allows plasma constituents (including fibrinoid material) to enter the vascular wall, thereby narrowing or obliterating the vascular lumen. Within the brain, the breakthrough vasodilation from failure of autoregulation leads to the development of cerebral edema and the clinical picture of hypertensive encephalopathy.

--The level at which fibrinoid necrosis occurs is dependent upon the baseline BP.

CLINICAL MANIFESTATIONS

--Most often occurs in patients with long-standing uncontrolled hypertension, many of whom have discontinued antihypertensive therapy. Underlying renal artery stenosis is also commonly present.--Marked elevation in BP.--Retinal hemorrhages and exudates (representing both ischemic damage and leakage of blood and plasma from affected vessels) and papilledema.--Malignant nephrosclerosis, leading to acute kidney injury, hematuria, and proteinuria. The renal vascular disease in this setting leads to glomerular ischemia and activation of the renin-angiotensin system, possibly resulting in exacerbation of the hypertension.--Acute myocardial infarction, pulmonary edema, unstable angina, dissecting aortic aneurysm, or eclampsia--Neurologic symptoms due to intracerebral or subarachnoid bleeding, lacunar infarcts, or hypertensive encephalopathy {insidious onset of headache, nausea, and vomiting, followed by nonlocalizing neurologic symptoms such as restlessness, confusion, and seizures and coma}**Magnetic resonance imaging may reveal edema of the white matter of the parieto-occipital regions, a finding termed reversible posterior leukoencephalopathy syndrome. When the MRI reveals primarily pontine abnormalities, the condition has been called hypertensive brainstem encephalopathy

--Initial goal of reducing mean arterial blood pressure by 10% to15%, but no more than 25%, in the first hour and then, if stable, to a goal of 160/100-110 mm Hg within the next 2 to 6 hours gradual healing of the necrotizing vascular lesions.--Aortic dissection is a special situation that requiresreduction of the systolic blood pressure to at least 120 mm Hg within 20 minutes.--More aggressive hypotensive therapy is both unnecessary and may reduce the blood pressure below the autoregulatory range, possibly leading to ischemic events (such as stroke or coronary disease) .--Then: switched to oral therapy, with the diastolic pressure being gradually reduced to 85 to 90 mmHg over two to three months.--Even with effective antihypertensive therapy, most patients who have had malignant hypertension still have moderate to severe chronic and acute vascular damage and are at continued risk for coronary, cerebrovascular, and renal disease.

ANTIHYPERTENSIVE DRUGS

-- A slower onset of action and an inability to control the degree of BP reduction has limited the use of oral antihypertensive agents in the therapy of hypertensive crises. --They may, however, be useful when there is no rapid access to the parenteral medications described above. Both sublingual nifedipine (10 mg) and sublingual captopril (25 mg) can substantially lower the BP within 10 to 30 minutes in many patients. --The major risk with these drugs is ischemic symptoms (eg, angina pectoris, myocardial infarction, or stroke) due to an excessive and uncontrolled hypotensive response. Thus, their use should generally be avoided in the treatment of hypertensive crises if more controllable drugs are available.

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