How to manage and approach resistant hypertension

1. RESISTANT HYPERTENSION

2.  Resistant hypertension is defined in the 2008 American Heart
Association guideline as 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
 Patients with resistant hypertension are at high risk for adverse
cardiovascular events.
 They are more likely than those with controlled hypertension to
have a secondary cause, which is usually at least in part
reversible.

3.  The goal blood pressure is less than 140/90 mmHg in average
risk hypertensive patients.
 There is evidence supporting a lower goal blood pressure in
patients with atherosclerotic cardiovascular disease, diabetes
mellitus or chronic kidney disease

4. GENERAL PRINCIPLES
 Identify and treat secondary hypertension
 Stop medications that raise the blood pressure
 Refer to a hypertension specialist
 Out-of-office BP monitoring
 Combination of pharmacologic and non-pharmacologic therapy

5.  The pharmacologic treatment of resistant hypertension
involves combinations of three or more drugs.
 Some patients have a specific indication for a class of
drugs (eg, beta blocker or non-dihydropyridine calcium
channel blocker for rate control in atrial fibrillation).

6.  If there is no such indication, the preferred three-drug regimen
consists of:
 Angiotensin-converting enzyme inhibitor or ARBs
 Long-acting CCB such as amlodipine and
 Long-acting thiazide diuretic, preferably chlorthalidone
 Among patients with an eGFR of less than 30mL/min/m2, a loop
diuretic, such as furosemide or torsemide is usually necessary
for effective volume control.

7.  Some patients with resistant hypertension are being
treated with a three drug regimen different from the
preferred regimen of an angiotensin inhibitor, long-acting
dihydropyridine calcium channel blocker, and a long-acting
thiazide diuretic.
 Our approach varies with the patient's regimen:
 If the patient is on hydrochlorothiazide, we switch
to chlorthalidone and then add other drugs, as
necessary.
 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.

8. RECOMMENDATION -1
 It is recommended that resistant hypertension should be
defined as uncontrolled hypertension both on office
measurements (BP ⩾140/90 mm Hg in individuals <80 years, or
SBP⩾150 mm Hg in individuals >80 years) and confirmed by out-
of-office measurements (home (HBPM) or ambulatory (ABPM) BP
measurement) despite a therapeutic strategy comprising
appropriate lifestyle and dietary measures and the concurrent
use of a triple-drug antihypertensive treatment, including a
thiazide diuretic, for at least 4 weeks, at optimal doses

9. RECOMMENDATION -2
 In addition to a thiazide diuretic, triple-drug
antihypertensive therapy should include a renin-
angiotensin system blocker (ARB or ACEI) and a calcium
channel blocker.
 Other pharmacological classes should be used in the
event of adverse effects or specific indications.
 Resistant hypertension should be treated with a thiazide
diuretic: chlorthalidone 12.5–50 mg per day,
hydrochlorothiazide ⩾25 mg per day or indapamide 2.5 or
1.5 mg SR per day.
 In patients with chronic kidney disease stage 4 or 5 (eGFR
o30 ml min− 1 1.73 m−2), the thiazide diuretic should be
replaced by a loop diuretic, such as furosemide,
torasemide or bumetanide, at a dosage adapted to the
patient’s renal function.

10. Recommendation-3:
 It is recommended that poor treatment compliance
should be identified using a questionnaire, urine drug
analysis and/or pill-count.
Recommendation-4:
 It is suggested that patient information, therapeutic
education for patients and HBPM are likely to improve
BP control.

11. RECOMMENDATION -5
 It is suggested that patients should be screened for
factors likely to influence treatment resistance (excessive
dietary salt intake, alcohol, depression and drug
interactions) or vasopressor drugs and substances

12. RECOMMENDATION -5
 Specific advice concerning lifestyle measures for patients with
resistant hypertension is similar to that for patients with well
controlled hypertension, and is as follows:
 Overweight (BMI>25) or obese (BMI>30) patients should lose
weight
 Excessive dietary salt intake should be reduced
 Alcohol consumption should be limited
 Patients should undertake regular physical activity
 The vegetable content of their diet should be increased and
the consumption of animal fats reduced.

14. RECOMMENDATION -6
 If resistant hypertension is confirmed, it is recommended that
the patient be referred to a hypertension specialist to screen for
secondary hypertension or target organ damage, and to determine
the future treatment strategy.

15. RECOMMENDATION -7
 Investigative techniques to identify secondary hypertension or
any potential triggering factors will be conducted according to
the clinical context, access to the techniques and the experience
of the hypertension specialist.
 They are as follows:
 Blood electrolytes and 2-h natriuresis, SCr, 24-h urine Cr and
proteinuria
 Abdominal angiogram
 Doppler ultrasound of renal arteries
 Plasma aldosterone and renin levels to calculate the plasma
aldosterone/renin ratio
 24-h urinary metanephrine and normetanephrin
 24-h urinary free cortisol measurements, dexamethasone
suppression test 1 mg
 Nocturnal oximetry, ventilation polygraph and
polysomnography.

16. RECOMMENDATION -8
 Suggested examinations to screen for target organ
damage are as follows:
 Serum creatinine, urine creatinine, microalbuminuria
and/or proteinuria
 Resting electrocardiogram and echocardiogram

17. RECOMMENDATION-9
 In the absence of a curable etiology in patients <80 years, it is
recommended that a four-drug combination therapy should be
initiated, including first-line spironolactone (12.5– 25 mg per day)
once the absence of any contraindication has been confirmed.
 Serum potassium and creatine levels require monitoring.
 A β-blocker may well be the preferred choice of drug depending
on the clinical situation.

18.  If a triple-drug combination therapy fails to achieve the target
BP level, a four-drug combination should be proposed.
o Although no randomized study to date has identified the optimal
therapeutic regimen after failure of a three-drug combination,
increasing the diuretic therapy is suggested when a sodium overload
is suspected.
 The strategy that has been the most widely assessed is that of
combining spironolactone with a triple-drug therapy.
 Several studies have reported the beneficial effects on BP levels
of adding spironolactone to create a four-drug combination.
 The benefits of a combination of several diuretics for certain
resistant hypertensive patients are possibly related to the
specific hormone profile of these patients (low renin levels with
or without detectable hyperaldosteronism).
 If spironolactone proves effective but a patient encounters
difficulties with tolerability, substitution with amiloride or
eplerenone (when authorised by national health authorities)
should be proposed

19. RECOMMENDATION -10
 In the event of a contraindication or a non-response to
spironolactone, or if adverse effects occur, it is suggested that a
β-blocker, an α-blocker, or a centrally acting antihypertensive
drug should be prescribed.

20. RECOMMENDATION -11
 Because renal denervation is still undergoing assessment for the
treatment of hypertension, it is suggested this technique should
only be proposed by a multidisciplinary team in a specialist
hypertension clinic.

22. UPTODATE
 In patients with persistent uncontrolled hypertension despite the
above three-drug regimen in optimal dosage, we suggest
adding spironolactone
 We typically begin at 12.5 mg/day and titrate up to, but not
above, 50 mg/day in the absence of proven primary
aldosteronism.
 Monitoring of serum potassium levels for both hypokalemia and
hyperkalemia are necessary if chlorthalidone and
spironolactone are used.
 For patients who cannot tolerate spironolactone,
eplerenone and amiloride are alternatives.

23. UPTODATE
 If the patient is still hypertensive, additional medications are
added sequentially.
 Possible agents that may be used include:
 Vasodilating BBs (labetalol , carvedilol , or nebivolol )
 Centrally acting agents ( clonidine or guanfacine ) and
 Direct vasodilators ( hydralazine or minoxidil ).

24. UPTODATE
 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 (although head-to-head full dose
comparisons are lacking)

25. UPTODATE
 Centrally acting agents may be effective, but adverse
effects are common and outcome data are lacking.
 Direct vasodilators hydralazine or minoxidil are reserved
for patients who remain hypertensive despite the above
approach.
 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.

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