II. Epidemiology

  1. See Refractory Hypertensive Populations
  2. Prevalence: May approach 20-30% of hypertensive patients

III. Definitions

  1. Resistant Hypertension
    1. Blood Pressure above goal despite adherance to Antihypertensive regimen of 3 medications

IV. Indications: Combination Antihypertensive Therapy

V. Risk Factors: Populations with Hypertension that is difficult to treat

  1. African-American
  2. Hispanic
  3. Diabetes Mellitus
  4. Renal Insufficiency or Renal Failure
  5. Elderly (especially Isolated Systolic Hypertension)
  6. Stage 3 Hypertension or greater
  7. Obese Patients

VI. Efficacy

  1. Adding a medication to protocol has five fold greater efficacy over doubling dose of current medications
  2. Combination agents are preferred over monotherapy esp. for BP>160/100 mmHg or >20/10 above goal

VII. Causes: Resistant Hypertension

  1. Noncompliance with current regimen (pseudoresistance, most common in up to 80% of patients)
    1. Recent drug holiday
    2. Unfilled prescription
    3. Frequently missed doses (ask this in a non-judgemental way)
    4. Lifestyle modification (e.g. DASH Diet, Weight loss, Exercise, Tobacco Cessation) not employed
      1. See Lifestyle Modification in Hypertension
  2. Inaccurate Blood Pressure Measurement (see BP Examination regarding pitfalls)
    1. Example: BP cuff that is too small will artificially inflate Blood Pressure readings
  3. White coat Hypertension
    1. Consider Ambulatory Blood Pressure Monitoring
    2. Increase regimen if average 24 hour BP > 129/79 or daytime average BP >134/84
  4. Pseudohypertension (elderly patients with atherosclerosis)
  5. Progression of disease
    1. Most Hypertension patients will require more than one agent for adequate Blood Pressure control
  6. Treatment program not optimized
    1. Example: Thiazide Diuretics are ineffective at GFR <30 ml/min (use Loop Diuretics instead)
  7. Medications or drugs counteracting Antihypertensive (e.g. NSAIDS, Sympathomimetics)
    1. See Medication Causes of Hypertension
  8. Comorbid condition (e.g. Sleep Apnea, morbid Obesity, Alcohol Abuse, anxiety, Chronic Pain)
  9. Secondary Hypertension
    1. See Secondary Hypertension Causes
    2. Obstructive Sleep Apnea
      1. Very common cause of Resistant Hypertension
    3. Hyperaldosteronism
      1. Represents 20% of refractory cases (consider especially if Hypokalemia)
      2. Use Spironolactone or Eplerenone
      3. Check Serum Potassium and Serum Creatinine 2 weeks after start and then every 6 months
    4. Chronic Kidney Disease is common
      1. Follow a salt restricted diet
      2. Use Diuretics with an ACE Inhibitor or Angiotensin Receptor Blocker
      3. Check Serum Potassium and Serum Creatinine 2 weeks after start and then every 6 months
    5. Hyperuricemia
      1. Experimental lowering of serum Uric Acid with Allopurinol results in signficant lowering of Blood Pressure
  10. Reference
    1. O'Rorke (2001) BMJ 322:1230 [PubMed]

VIII. Preparations: Combinations (assist with cost and compliance)

  1. Prinizide (Lisinopril 10-20 mg with Hydrochlorothiazide 12.5-25 mg)
  2. Diovan-Hct (Valsartan 80-160 mg with Hydrochlorothiazide 12.5 mg)
  3. Ziac (Bisoprolol with Hydrochlorothiazide 6.25)
  4. Lotrel (Benzapril 10-20 mg with Amlodipine 2.5-10 mg)
  5. Tarka (Trandolopril 1-2 mg with Verapamil 180-240 mg)
  6. Exforge (Valsartan and Amlodipine)
  7. Reserpine 1.25-2.5 mg with Hydrochlorothiazide 25 mg
  8. Tenoretic (Atenolol 50-100 mg with Chlorthalidone 25 mg)

IX. Preparations: Combinations that add 4 drugs in 2 pills for $50-60

  1. Tenoretic 100/25 with Lotrel 10/20
  2. Tenoretic 100/25 with Prinizide 20/12.5

X. Protocol: Approach

  1. Consider reasons for Resistant Hypertension (see below)
  2. Review Hypertension Risk Stratification
  3. Determine Hypertension Reduction Goal
  4. Advance to next step if BP>15/10 above goal
  5. Consolidate medications into combination agents and once daily regimens
  6. Consider optimal strategies in specific populations when selecting medications
    1. See Hypertension Management for Specific Populations
  7. Consider at least one non-diuretic Antihypertensive at bedtime (e.g. Beta Blocker)

XI. Protocol: Step 1 (combination agents)

  1. Serum Creatinine <1.5 to 1.8 mg/dl
    1. ACE Inhibitor (or ARB) and Thiazide Diuretic
    2. Chlorthalidone (or Inapamide) is preferred as more potent and longer acting than Hydrochlorothiazide
  2. Serum Creatinine >1.5 to 1.8 mg/dl (or GFR <30 ml/min)
    1. ACE Inhibitor and Loop Diuretic (Lasix typically twice daily or Torsemide once daily)
  3. Alternative
    1. Angiotensin Receptor Blocker may be used instead of an ACE Inhibitor (equivalent efficacy, fewer adverse effects)
    2. Avoid combination of ACE Inhibitor with Angiotensin Receptor Blocker

XIII. Protocol: Step 3

  1. Some guidelines recommend using the step 4 agents (e.g. Spironolactone) before the step 3 agents
    1. Spironolactone is often more effective in Resistant Hypertension
  2. Heart Rate >80-85 bpm (or if CAD, CHF or other Beta Blocker specific indication)
    1. Add low dose Beta Blocker
      1. However, Beta Blockers are unlikely to substantially decrease resistant Blood Pressure
    2. Consider Labetalol or Carvedilol instead of a Beta Blocker
      1. Combined alpha-beta adrenergic blocker effect
  3. Heart Rate <80-85 bpm
    1. Add Dihydropyridine Calcium Channel Blocker (e.g. Amlodipine, Nifedipine)

XIV. Protocol: Step 4

  1. Consider Spironolactone 12.5 to 50 mg orally daily
    1. Counters the Sodium retention often present in Resistant Hypertension
    2. Dosing of 100 mg offers no added benefit compared with 50 mg dose
    3. Monitor Renal Function and Potassium (at baseline, again in 2 weeks and then periodically)
  2. Consider Alpha-Beta Adrenergic blocker (Labetolol)
    1. If not already added above (do not combine with Beta Blockers)

XV. Protocol: Step 5

  1. Consider Central Adrenergic Agonist (e.g. Clonidine, Guanfacine)
    1. Risk of sedation and Xerostomia
  2. Consider Hydralazine (Apresoline)
  3. Consider Reserpine (risk of Major Depression)
  4. Consider long acting Alpha adrenergic blocker at night (e.g. Terazosin), especially in BPH

XVI. Protocol: Step 6

  1. Consult Nephrology or Cardiology

XVII. Protocol: Additional Measures

  1. Consider Renal Sympathetic Denervation
  2. Consider Tekturna (Aliskiren), a Direct Renin Inhibitor
    1. No significant benefit in Hypertension, Chronic Kidney Disease, Heart Failure
    2. Risk of hyptension, Hyperkalemia and increased Serum Creatinine
    3. (2016) Presc Lett :3(6):34

XVIII. References

  1. Woolley (2007) Park Nicollet Primary Care Conference, Minneapolis, MN
  2. Schwartz (2008) Mayo Selected Topics in Internal Medicine, Lecture
  3. Garg (2005) Am J Hypertens 18:619-626 [PubMed]
  4. James (2014) JAMA 311(5): 507-20 [PubMed]
  5. Moser (2006) N Engl J Med 355(4): 385-92 [PubMed]
  6. Viera (2009) Am Fam Physician 79(10): 863-9 [PubMed]

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