Resistant hypertension is defined as blood pressure that remains above goal despite treatment with three antihypertensive agents of different classes, one being a diuretic. Refractory hypertension is when blood pressure cannot be controlled despite four or more drugs at maximal doses. Pseudoresistant hypertension occurs when poor control is due to non-adherence or suboptimal treatment rather than true treatment resistance. Evaluation of patients with resistant hypertension includes screening for secondary causes like primary aldosteronism or renal artery stenosis through tests of electrolytes, renal function, and imaging studies. Treatment involves optimizing the current three-drug regimen before adding supplementary drugs like beta blockers or aldosterone antagonists.

1. REFRACTORY
HYPERTENSION
03-01-2014

4. 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.

5. • 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

6. • 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

7. 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

8. • 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

9. Terminologies
• Apparent resistant hypertension
• Pseudoresistant hypertension
• True resistant hypertension

10. 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

11. 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 pressure
2. Poor adherence to antihypertensive therapy
3. Suboptimal antihypertensive therapy
4. Poor adherence to lifestyle and dietary approaches
5. White coat hypertension

12. 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.

13. 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

14. 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

15. 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

16. Risk factors

17. • 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.

18. 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

19. 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

20. 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.

21. 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

22. 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

26. • Medical history — The medical history should document
age of onset, duration, severity, and progression of the
hypertension
•
Current medication use (including herbal and over-thecounter medications) and the response to prior
medications should be determined. Patient adherence is
established mostly by self-report

27. • 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

28. •
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

29. • 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.

30. • 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

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

32. • 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 disease
3.coronary artery disease or
4.cerebrovascular disease,
5.a rise in serum creatinine after initiation of ACEI or ARBS
6.onset of hypertension at a young age which could represent
fibromuscular dysplasia

39. • 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

40. 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.

41. 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

42. • 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

43. • 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

44. • 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

45. • 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)

51. EXPERIMENTAL THERAPIES
1. Radiofrequency ablation of renal sympathetic nerves
2. Stimulation of carotid sinus baroreceptors

55. 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)

56. Baroreceptor mechanism