This document discusses resistant hypertension and its treatment. It defines resistant hypertension as blood pressure that remains above goal despite use of three antihypertensive agents from different classes including a diuretic. Treatment involves identifying and treating secondary causes, adjusting medications that raise blood pressure, monitoring blood pressure outside the office, making lifestyle changes, and using pharmacologic therapies like diuretics, aldosterone antagonists, and catheter-based renal denervation. While renal denervation showed promise in early trials, the SYMPLICITY HTN-3 trial found it did not significantly reduce blood pressure compared to a sham procedure.

1. D . B A S E M E L S A I D E N A N Y
L E C T U R E R O F C A R D I O L O G Y
A I N S H A M S U N I V E R S I T Y
Resistant Hypertension:
Treatment

2. 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%).

3. 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 THERAPY
5-PHARMACOLOGIC THERAPY

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

5. 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}

6. --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

7. 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 .

8. 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]

9. --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].

10. 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

12. 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.

14. 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

15. For anyone who participates in clinical trials, the oversight of a clinical
trial is such that the patients are very rigorously followed, and there is
pill-counting and recommendations for strict compliance, all of which
is very different from what happens with "optimal medical therapy" in
real-world practice.
Furthermore, this was a renal denervation strategy with a particular
device, so it could be that this particular device isn't the best device for
renal denervation.
A third practical question, which is unanswered, is whether we really
achieved renal denervation. The animal and preclinical trials looked at
how much energy was needed to create an injury that went from the
renal artery lumen down to the renal nerves. Perhaps in this middle-
aged group of patients with hypertension on a western diet, there is
greater thickening of the renal vessel, which could actually cause
problems in delivering the energy required to achieve effective renal
denervation.

17. 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

18. 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

19. Symplicity Catheter System Design (Medtronic Vascular)

20. **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

21. --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.

22. 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.

23. 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 .

24. *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.

25. *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.

26. 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}.

27. *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 usually
appropriate in these situations instead to gradually reduce blood pressure
over 24 to 48 hours.
Most patients with hypertensive urgency can be treated as outpatients.

28. *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.

29. 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.

30. 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

31. --Initial goal of reducing mean arterial blood pressure by 10% to
15%, 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 requires
reduction 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.

32. ANTIHYPERTENSIVE DRUGS

38. -- 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.

39. Thank you