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Resistant Hypertension
Which Drugs, Which Combinations?
Uncontrolled hypertension can cause stroke, MI, heart failure and renal impairment. Yet, when BP
is lowered, there is a significant reduction in stroke-related and cardiac mortality. In this article,
Dr. Rebello outlines the drug combinations that may be used to effectively control this disease.
Rosario Rebello, MD, FRCPC
Presented at Dalhousie University’s 34th Annual February Refresher Program,
Halifax, Nova Scotia, February 2008.
uidelines recommend that patients with
hypertension (HTN) and no comorbidities be
treated to a goal BP of < 140/90 mmHg and
< 130/80 mmHg in those with diabetes mellitus,
chronic renal disease and CV or cerebrovascular
disease. Uncontrolled HTN causes target organ
damage such as stroke, MI, heart failure and renal
impairment. However, when BP is lowered, there is
a 40% to 50% reduction in stroke-related mortality
and a 15% to 20% decrease in cardiac mortality.
G
Table 1
Patient characteristics associated
with resistant hypertension (HTN)
• Older age
• Obesity
• Excessive salt or alcohol intake
• Chronic kidney disease
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What is resistant HTN?
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Resistant HTN is defined as BP which remains
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above goal despite the use ofe
three
orrmoreibdrugs,
e cowe label a patient with resistant
ited. iBefore
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n
h
l
t a s HTN, the following should be excluded:
including a diuretic,
ina
rational
e pro prinand
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uscombination
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o
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f nauItsthprevalence
a 20% to 1. Pseudoresistance:
ori
optimal
ieiswabout
Notdosage.
U
lay, v
30% and it tends to
sp more often in certain
dioccur
patients (Table 1). Since these patients have
uncontrolled HTN and often other comorbidities,
they are at increased CV risk.
ncontrolled HTN
causes target organ
damage such as stroke, MI,
heart failure and renal
impairment.
U
• Female gender
©
• African-American race
• Measurement errors (e.g., improper cuff
size)
• White coat effect—higher office
readings compared to those at home
• Pseudohypertension—some elderly
patients require a higher cuff inflation of
10 mmHg to 15 mmHg to compress
stiff, atherosclerotic vessels, compared
to intra-arterial pressure. An absence of
target organ damage or symptoms of
postural hypotension may alert one to its
presence
Perspectives in Cardiology / August/September 2008 23
Resistant Hypertension
2. Resistant HTN—patient-related factors
• Nonadherence to drug therapy
• Excess salt or alcohol intake, obesity,
lack of exercise
• Ingestion of drugs or substances which
interfere with BP control (Table 2)
3. Resistant HTN—physician-related factors
• Inadequate dose of antihypertensive
drugs
• Volume overload—it is important to
make sure that the patient is not volume
over-loaded. Fluid-retaining drugs, such
as NSAIDs, should be withdrawn and if
the patient is not on a thiazide, one
should be added (e.g., hydrochlorothiazide
12.5 mg to 25 mg q.d.). In the presence of
renal impairment (creatinine > 150 µmol/L
or estimated glomerular filtration rate
[eGFR] < 30 mL to 50 mL per minute),
switch to furosemide in divided dose, as
furosemide is short-acting
Does the patient have a
secondary cause for the
HTN?
Having excluded pseudoresistance, patient or
physician-related factors as causes of resistant
HTN, a search for secondary HTN should begin
(Table 3). Some clues to the presence of secondary HTN include:
• Obstructive sleep apnea: snoring, morning
headache, lack of restorative sleep and
daytime somnolence in an obese patient
Dr. Rebello is an Assistant Professor, Department
of Medicine, Dalhousie University; and Attending
Physician, Queen Elizabeth II Health Sciences
Centre, Halifax, Nova Scotia.
24 Perspectives in Cardiology / August/September 2008
Table 2
Medications that can interfere with
BP control
• NSAIDs, selective COX-2 inhibitors
• Alcohol
• Sympathomimetic agents
(e.g., decongestants)
• OCs
• Cyclosporine
• Antineoplastic drugs (e.g., sunitinib,
bevacizumab)
• Erythropoietin
• Natural liquorice
• Stimulants (e.g., amphetamines, ephedrine)
• Herbal compounds (e.g., ephedra)
• Hyperaldosteronism: hypokalemia in a patient
taking an ACE inhibitor or an ARB, when one
would expect the opposite. However, note that
the potassium can be normal in about 60% of
patients with hyperaldosteronism. If there is a
strong suspicion, request an aldosterone/renin
ratio
• Renovascular HTN: HTN in a young female
(< 30-years-of-age); an older individual
(≥ 65-years-of-age), especially one whose
BP was previously well-controlled; presence
of generalized atherosclerosis, especially in
a diabetic; or if there is a rise in the serum
creatinine of > 25% after starting an ACE
inhibitor or ARB. An epigastric bruit will
not always be present
• Phaeochromocytoma: paroxysms of
headache, palpitations and sweating.
Request 24-hour urine for metanephrines, or
serum metanephrines if available
Resistant Hypertension
A
Step 1
C or D
Step 2
A + C or A + D
Step 3
A+C+D
Step 4
A+B+C+D
Step 5
Add:
• Further diuretic therapy
• α-blocker or
• spironolactone
A: ACE inhibitor or ARB
B: ß-blocker
C: Calcium channel blocker
D: Thiazide diuretic
Figure 1. Drug combinations.
Treatment of resistant HTN
Patients should be encouraged to reduce salt and
alcohol intake, to exercise and to lose weight.
Adherence may be improved by educating patients
that treatment is life-long and to use fixed dose
combinations where appropriate, in order to
reduce costs and increase compliance. If obstructive sleep apnea or a secondary cause is found, this
should be treated appropriately.
Drug combinations
Table 3
Secondary causes of HTN
Common
• Obstructive sleep apnea
• Renal parenchymal disease (e.g., diabetic
nephropathy)
• Renovascular (e.g., atherosclerotic [common] or
fibromuscular dysplasia)
• Hyperaldosteronism (e.g., adrenal adenoma, or
bilateral adrenal hyperplasia [common])
Less common
Generally, four classes of drugs, each with a
different mechanism of action, are used for treating HTN (Figure 1, Table 4).
1. If initial therapy was with a calcium channel
blocker (CCB) or a thiazide (Step 1), and a
second drug is required, add an ACE inhibitor
or an ARB (Step 2)
• Pheochromocytoma
• Cushing’s syndrome
• Hyperparathyroidism
• Hyperthyroidism/hypothyroidism
• Coarctation of the aorta
Perspectives in Cardiology / August/September 2008 25
Resistant Hypertension
Table 4
Classes of antihypertensive drugs
Take-home message
A. ACE inhibitors and ARBs decrease vascular
resistance by inhibiting RAAS
• Resistant HTN is common
B. ß-blockers decrease sympathetic over
activity, as well as inhibit renin release
• Exclude nonadherence, interfering drugs
or substances and white coat effect
C. CCBs promote smooth muscle relaxation by
inhibiting the influx of calcium
D. Diuretics decrease volume overload
• Look for secondary causes, such as
obstructive sleep apnea and renovascular
HTN
Others: α-blockers (vasodilator),
spironolactone (anti-aldosterone)
• Hyperaldosteronism is a common cause of
resistant HTN
RAAS: Renin angiotensin aldosterone system
CCB: Calcium channel blocker
2. If initial therapy was with an ACE inhibitor or
an ARB (Step 1) and a second drug is
required, add a CCB or a thiazide (Step 2)
3. If three drugs are required, the combination
of an ACE inhibitor or ARB, CCB and a
thiazide works well (Step 3)
4. If a fourth drug is required, add a ß-blocker
(Step 4)
5. If BP remains uncontrolled, consider:
• Switching to a loop diuretic, especially
in the presence of renal impairment or
volume overload
• Adding an α-blocker, or
• Adding spironolactone.
Recent studies have suggested that the prevalence of hyperaldosteronism in patients with
resistant HTN is about 20%. The aldosterone
antagonist spironolactone in a dose of
12.5 mg to 50 mg q.d. has been shown to lower
BP on average by 25 mmHg systolic and
12 mmHg diastolic. In this study, patients were
already taking an average of four medications,
including an ACE inhibitor or an ARB and a
thiazide. Spironolactone was well-tolerated,
though breast tenderness due to gynecomastia
may occur in men. Hyperkalemia is uncommon,
26 Perspectives in Cardiology / August/September 2008
• Use proper technique when taking BP
• Spironolactone is a useful add-on drug
• Multiple drugs, including a diuretic, are
required
but close monitoring of the potassium level is
necessary. If spironolactone is not tolerated,
amiloride 10 mg q.d. may be used instead. PCard
Resources
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Diagnosis, Evaluation And Treatment. A Scientific Statement From the
American Heart Association Professional Education Committee of
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2. Moser M, Setaro JF: Clinical Practice. Resistant or Difficult-to-Control
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Resistant Hypertension. J Clin Hypertens (Greenwich) 2008;
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