Effective Strategies to Treat

Difficult-to-Control Hypertension

Joel Handler MD
Hypertension Lead
Care Management Institute
Kaiser Permanente

Resistant hypertension is defined by a

blood pressure of at least 140/90 or at
least 130/80 in patients with diabetes or
renal disease despite adherence to
treatment with full doses of at least
three antihypertensive medications,
including a diuretic.
JNC 7

Resistant hypertension is primarily a

systolic and age related problem
Diastolic BP goal achieved 90% in the
major trials
Systolic BP goal achieved 60-65% in
the major trials
True resistance occurs in about 15%

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension

Measurement Artifacts
Upper arm measurements on bared arm
Proper cuff size
5 minutes of rest for first measurement; wait at
least one minute for second measurement
Arm supported on furniture with cuff at heart level
Back supported, legs uncrossed, feet on floor
No talking
Bladder emptied if necessary

Requirements for White Coat Effect

Determination
Multiple (4) nurse BPs will obviate most
white coat effect
AAMI, BHS, EHS approved home BP
apparatus with memory chip
Yearly validation of home BP machine
Protocoled home BPs emphasizing morning
determinations
Mean home BP < 135/85 mm Hg

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension

Medical Adherence
Adherence 80% with prescribed medication
is minimum level required for pharmacologic
benefit
85% of patients admitting to less than
complete adherence are taking less than 75%
prescribed medication
39% patients reporting perfect adherence
take less than 75% of their medication
Physician messaging makes a difference

Beta Blocker Therapy and Symptoms of Depression,

Fatigue, and Sexual Dysfunction: Meta Analysis

Depression: 7 trials; 10,622 patients

Fatigue: 10 trials; 17,682 patients
Sexual Dysfunction: 6 trials, 14,897 patients
Fatigue:
4 withdrawals/1000 patients/year
Mostly with propanolol
Sexual Dysfunction: 2 withdrawals/1000; nocebo
effect described in previous ED study
Depression: No significant difference

Ko et al. JAMA 2002; 288: 351-357

Managing Medication Myths

and Side Effects to Encourage
Adherence

Thiazide, thiazide-like
Beta blockers
Calcium channel blockers

Thiazide Related Gout

Thiazide related hyperuricemia is dose
related
HDFP Trial: 15 episodes of gout over 5
years in 3693 patients treated with
chlorthalidone 25-100mg (equivalent to 50200 mg HCTZ)
Low dose thiazide (HCTZ 12.5-25 mg) is
not contraindicated in gout

Thiazide Myths Exposed

Significant cross reactivity with sulfa antibiotics has not
been demonstrated; sulfa allergic patients have the
same mildly increased reactivity to penicillin and thiazide
(NEJM 2003;349:1628-35); thiazide can be
administered to patients with sulfa allergy
Thiazide is first line treatment for calcium kidney stones
due to idiopathic hypercalciuria and also treats idiopathic
calcium lithiasis; avoid thiazide with hyperparathyroidism
(raises serum Ca)

Criteria for Panic Attacks and Panic Disorder:

a cause of medication intolerance
Panic attack is a discrete period of intense fear or
discomfort involving 4 of the following symptoms:
Shortness of breath (dyspnea) or smothering sensation
Dizziness, unsteady feelings, or faintness
Palpitations or accelerated heart rate (tachycardia)
Trembling or shaking
Sweating
Choking
Nausea or abdominal distress
Hot flushes or chills
Chest pain or discomfort

Case Study

65 year old male with long standing

anxiety disorder on paroxetine (Paxil)
intolerant to HCTZ due to mouth dryness,
also intolerant to atenolol with tremors,
and both lisinopril and nifedipine with
fatigue was referred to Hypertension
Clinic because of refractory hypertension
due to medication intolerance.

Case Study

His psychiatrist attributed these symptoms

to his underlying anxiety disorder.
Paroxetine and bupropion (wellbutrin)
were nonefficacious, but clonazepam
(klonopin) led to a reduction in somatic
complaints. HCTZ was successfully
reinitiated, and in combination with
lisinopril and atenolol led to control of his
hypertension.

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension

Lifestyle Modifications
Modification
Weight Reduction

Approximate SBP
Reduction
(range)

5-10 mmHg/10kg

Adopt DASH eating plan

8-14 mmHg

Dietary sodium reduction

2-8 mmHg

Physical activity

4-9 mmHg

Moderation of alcohol
consumption

24 mmHg

Dosage
Score
2.8
2.1
1.7
50.0

2.0
51.8

60.0

2.0

1.0

39.1

(84)

3.0

(208)

(149)

Modan M, et.al. Hypertens 1991;17:565-573

(140)

Incidence (% of subjects)

60
Control

50

49

Surgery

41

40
29

30

24

24

20
10

7
1

2Yr

10 Yr

Diabetes
No. of subjects
Control
Surgery
Odds ratio
95% Cl
P value

1402
539
1489
517
0.14
0.25
0.08-0.24 0.17-0.38
<0.001
<0.001

2Yr

10 Yr

Hypertension
770
279
623
215
0.78
0.75
0.60-1.01 0.52-1.08
0.06
0.13

SOS study. Sjostrom et al. NEJM 20047;351;2683-2691

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension

Interfering or Exogenous Substances

NSAIDs
Sympathomimetic drugs: phenylephrine,
cocaine, amphetamines
Alcohol >1 drink/day for women,
>2 drinks/day for men
Dietary salt > 5 grams daily
Cyclosporine, tacrolimus, steroids
Buspirone (Bu Spar)
Venlafaxine (Effexor XR)

ContinuedMetoclopramide (Reglan)
Oral contraceptives
Black licorice (50 gms daily x 2 weeks)
Tricyclic antidepressants
Erythropoiten
Herbs: ginseng, ginger, yohimbine
Topical testosterone
Cancer chemotherapy: angiogenesis inhibitors
Clonidine + beta blocker (due to combo
pressor effect and clonidine drug holiday on BB,
but also avoid combined rate slowers)

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension

Obstructive Sleep Apnea

Associated with resistant hypertension
Prototype: obese middle age male with large
neck
Pathophysiologic role of sympathetic nervous
system and RAAS (renin angiotensin
aldosterone system)
Underpowered studies show BP reduction
with CPAP
Get sleep study in resistant hypertension,
treat sleep apnea with CPAP, probably will not
reduce BP

n.s.
n.s.
p=0.024
p=0.022

p=0.037

p<0.001

Reduction of blood pressure (BP) and heart rate (HR) after 6 months of bi-level or
continuous positive airway pressure treatment in patients taking and not taking BPlowering drugs (BPLD). SBP = systolic: DBP = diastolic BP.
Borgel et al. AJH 2004;17:1081-1087

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension

Cause of Resistance
Cause of resistance found in 133/141 94% (83/91 91%) cases
Office
resistance
6%
Psychological
causes
9%

Unknown
6%

Nonadherence
16%

Secondary
HTN
5%

Interfering
substances
1%

Drug-related
causes
58%

Primary cause of resistant hypertension

Garg JP, et al. Am J Hypertens 2003;16:925-930

Achievement of goal blood pressure (BP), by cause of resistance

Garg JP, et al. Am J Hypertens 2005;18:619-626

Diuretic Maximization
Chlorthalidone 25 mg
Roughly twice as potent as HCTZ and longer
acting: 25mg chlorthalidone = 50mg HCTZ
More hypokalemia
Thiazide-like, can be used with mild HCTZ rash or
dizziness
Combination pill: tenoretic 25/50mg, 25/100mg
Furosemide BID (cr cl < 30 cc/min; thiazide
related hyponatremia)

Figure 2. Effects of HCTZ and chlorthalidone on SBP as a function of daily dose (mg)
Carter BL. Hypertens 2004; 43:4-9

What additional agents to add?

What combinations work?

Spironolactone
Used for resistant hypertension with
normal aldosterone levels, 12.5-50mg/daily
Additional benefits: antiproteinuric,
improves heart failure survival (RALES)
10% gynecomastia
Not when creatinine > 2.5, K > 5.0
Consider using with chlorthalidone

BP response (mm Hg)

0
-5
-10

-10

-10
-12

-15
-20

-21
-23

-25
-30

-25

6wk
Systolic BP

3mo

6mo

Diastolic BP

Spironolactone-induced reduction in systolic blood pressure BP and diastolic

BP at 6 weeks, 3 months and 6 months follow-up in subjects with resistant
hypertension (n=76). BP reduction was significant at all timepoints compared
to baseline.

Nishizaka MK, et al. Am J Hypertens 2003;16;925-930

SBP

DBP

Chapman N. ASCOT. Hypertens 2007; 49:839-845

Life-threatening Hyperkalemia during a Combined

Therapy with the Angiotensin Receptor Blocker
Candesartan and Spironolactone

HIDEKI FUJII *, HAJIME NAKAHAMA *, FUMIKI YOSHIHARA *,

SATOKO NAKAMURA * TAKASHI INENAGA *,
and YUHEI KAWANO *

Kobe J Med Sci 2005; 51:1-6

Drug Combinations
Chlorthalidone 25mg + spironolactone 12.5-50 mg

Excellent diuretic maximization, also vs hypokalemia

Dihydropyridine/nondihydropyridine CCBs

12/20 (60%) in Garg et al. brought to goal BP

Option in elderly with thiazide intolerance
Edema problem

ACEI plus ARB

Mostly 4-8 week studies

Risk of ARF in animal studies
ACEI/ARB were not maxed out
Additional reduction mild: 4/3 mm Hg
Best application in proteinuric patients

Direct Vasodilators
Hydralazine sequence is 25 BID to 50
BID to 100mg BID
Minoxidil sequence is 2.5mg, to 5mg, to
5mg BID, to 10 mg BID, to 20 mg BID
Need a BB and a diuretic on board
Watch for headache and fluid retention

Minoxidil
Excellent drug for resistant hypertension
Direct vasodilator causing reflex tachycardia and
fluid retention
Need BB on board to prevent myocardial ischemia
Dosage range 2.5mg to 20 mg BID
Temporarily discontinue drug with marked edema,
than restart with more diuretic
90% ST-T change within 2 weeks, later resolve

A1-Adrenergic Receptor Blockers

Not to be used for monotherapy:
ALLHAT (class effect)
May be used as an add-on for resistant
hypertension
May cause urinary incontinence,
especially in females, due to bladder
outlet relaxation

Additional Agents/ Devices

Combined alpha- and beta-blockers (labetalol, carvedilol)
Reserpine 0.05-0.1 mg
Isosorbide vs augmentation pressure
Device-guided slow breathing exercises (Resperate)
Device-mediated electrical carotid sinus baroreceptor stimulation
Thoracic bioimpedance measurements

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension

Workup Scenarios Where Secondary

Hypertension Syndromes May be Considered

Under age 30 resistant to two or more drugs with no

other obvious etiology, i.e., morbid obesity
Hypertension refractory to maximal doses of four or
five drugs
Hospitalization for hypertensive crisis (though crisis
is mostly due to medication noncompliance)
New diastolic BPs > 100 mm Hg over age 60

Hypertension with severe target organ damage

(i.e. blindness, acute renal insufficiency, or
encephalopathy)
Hypertension with recurrent pulmonary edemarule out renovascular
Resistant hypertension with hypokalemia: rule out
hyperaldosteronism, renal vascular etiology,
pheochromocytoma, Cushings syndrome
Resistant hypertension with 3 to 4+ proteinuriaan indicator of primary rather than secondary renal
disease (causes of nephrotic syndrome)

Suggested Screening Tests for Secondary

Hypertension Syndromes
(Rarely Necessary)

Captopril renogram (only if kidney function is normal) or

renal artery magnetic resonance angiography (MRA)
Hyperaldosteronism: morning aldosterone/plasma renin
activity ratio 20 when absolute aldosterone level 15 ng/dl
with potassium 3.5 meq/l performed on all drugs except
spironolactone (must be off spironolactone >6 weeks).
Pheochromocytoma (extremely rare): 24 hour urine for
total metanephrines and catecholamines

Thyroid-stimulating hormone (TSH):

hypothyroidism as well as hyperthyroidism cause
hypertension
Calcium:hyperparathyroidism may cause
hypertension, but HTN usually persists post
parathyroidectomy for primary hyperpara
If patient is under age 35 and systolic pressure in
right leg or left arm is more than 10 mmHg lower
than the systolic pressure of the right arm, order
echocardiogram to rule out aortic coarctation

Cushings syndrome: dexamethasone

suppression test (DST) giving 1mg
dexamethasone between 11 p.m. and midnight,
8 a.m. plasma cortisol should be
< 2.5 mcg/dl (approximately 15% false
positives); alternative is to order 24-hour urine
free cortisol independently, or as follow-up to a
positive DST

Clinical Clues for the Diagnosis of

Renovascular Hypertension
Historical and clinical findings:
Abrupt onset hypertension after age 55
Increasing blood pressure in previously controlled hypertension
Malignant hypertension
Recurrent flash pulmonary edema
Worsening renal function with angiotension-converting enzyme
inhibitor or angiotensin receptor blocker therapy
Epigastric atherosclerosis elsewhere
Tobacco use

Clinical Characteristics of 131 Patients with Proved

Renovascular Hypertension: note overlap
Characteristics

Essential
Hypertension,%

Renovascular
Hypertension,%

Duration of hypertension <1 year

12

24

Age at onset after 50

15

Family history of hypertension

71

46

Grade 3 or 4 funduscopic changes

15

Abdominal bruit

46

Blood urea nitrogen>20mg/100mi.

15

Serum K<3.4mEq/L

16

Proteinuria

32

46

JAMA 1972;220:1209

Cardiovascular Outcomes in Renal

Atherosclerotic Lesions (CORAL)
2005-2010; 1080 patients
Renal stenting vs medical therapy
Primary end point: event-free survival
Inclusion criteria:
Systolic BP 155 mmHg
2 or more antihypertensives
1 renal arteries stenosed 60% <80%
with 20 mmHg gradient, or 80% < 100% stenosis by
angiography

Summary of Med Changes

Use chlorthalidone 25mg
Add spironolactone 12.5 50 mg
Consider adding hydralazine or
minoxidil
Consider alpha1-blocking agents,and
combination alpha-beta blockers
Consider CCB combination therapy
especially with diuretic intolerance

Evaluation of Resistant Hypertension

Measurement artifacts
Medication adherence
Lifestyle issues
Interfering or exogenous substances
Obstructive sleep apnea
Drug-related causes: med changes
Secondary hypertension