Effective Strategies to Treat DifficulttoControl Hypertension

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Effective Strategies to Treat
Difficult-to-Control Hypertension

• Joel Handler MD
• Hypertension Lead Care Management
  Institute
• Kaiser Permanente

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• 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

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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

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Evaluation of Resistant Hypertension

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

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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

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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 lt 135/85 mm Hg

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Evaluation of Resistant Hypertension

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

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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

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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
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Managing Medication Myths and Side Effects to
Encourage Adherence

• Thiazide, thiazide-like
• Beta blockers
• Calcium channel blockers

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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 50-200 mg HCTZ)
• Low dose thiazide (HCTZ 12.5-25 mg) is not
  contraindicated in gout

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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
  20033491628-35) 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)

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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

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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.

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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.

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Evaluation of Resistant Hypertension

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

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Lifestyle Modifications
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Modan M, et.al. Hypertens 199117565-573
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SOS study. Sjostrom et al. NEJM
200473512683-2691
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Evaluation of Resistant Hypertension

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

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Interfering or Exogenous Substances

• NSAIDs
• Sympathomimetic drugs phenylephrine, cocaine,
  amphetamines
• Alcohol gt1 drink/day for women,
• gt2 drinks/day for men
• Dietary salt gt 5 grams daily
• Cyclosporine, tacrolimus, steroids
• Buspirone (Bu Spar)
• Venlafaxine (Effexor XR)

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• Continued-
• Metoclopramide (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)

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Evaluation of Resistant Hypertension

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

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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

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n.s.
n.s.
p0.024
p0.022
p0.037
plt0.001
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 BP-lowering drugs (BPLD).
SBP systolic DBP diastolic BP.
Borgel et al. AJH 2004171081-1087
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Evaluation of Resistant Hypertension

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

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Cause of Resistance Cause of resistance found in
133/141 94 (83/91 91) cases
Primary cause of resistant hypertension Garg JP,
et al. Am J Hypertens 200316925-930
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Achievement of goal blood pressure (BP), by cause
of resistance Garg JP, et al. Am
J Hypertens 200518619-626
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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 lt 30 cc/min thiazide
  related hyponatremia)

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Figure 2. Effects of HCTZ and chlorthalidone on
SBP as a function of daily dose (mg) Carter BL.
Hypertens 2004 434-9
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• What additional agents to add?
• What combinations work?

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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 gt 2.5, K gt 5.0
• Consider using with chlorthalidone

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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 (n76). BP reduction was
significant at all timepoints compared to
baseline. Nishizaka MK, et al. Am J Hypertens
200316925-930
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SBP
DBP
Chapman N. ASCOT. Hypertens 2007 49839-845
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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 511-6
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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

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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

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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

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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

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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

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Evaluation of Resistant Hypertension

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

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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 gt 100 mm Hg over age 60

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• Hypertension with severe target organ damage
  (i.e. blindness, acute renal insufficiency, or
  encephalopathy)
• Hypertension with recurrent pulmonary edema- rule
  out renovascular
• Resistant hypertension with hypokalemia rule out
  hyperaldosteronism, renal vascular etiology,
  pheochromocytoma, Cushings syndrome
• Resistant hypertension with 3 to 4 proteinuria-
  an indicator of primary rather than secondary
  renal disease (causes of nephrotic syndrome)

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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 gt6
  weeks).
• Pheochromocytoma (extremely rare) 24 hour urine
  for total metanephrines and catecholamines

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• Thyroid-stimulating hormone (TSH) hypothyroidism
  as well as hyperthyroidism cause hypertension
• Calciumhyperparathyroidism 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

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• Cushings syndrome dexamethasone suppression
  test (DST) giving 1mg dexamethasone between 11
  p.m. and midnight, 8 a.m. plasma cortisol should
  be
• lt 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

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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-convert
  ing enzyme inhibitor or angiotensin receptor
  blocker therapy
• Epigastric atherosclerosis elsewhere
• Tobacco use

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Clinical Characteristics of 131 Patients with
Proved Renovascular Hypertension note overlap
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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 lt80
• with 20 mmHg gradient, or 80 lt 100
  stenosis by angiography

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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

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Evaluation of Resistant Hypertension

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