Resistant Hypertension

Aka: Resistant Hypertension, Hypertension Combination Therapy, Combination Antihypertensive Therapy, Refractory Hypertension, Refractory Hypertensive Populations

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II. Epidemiology

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

III. Definitions

  1. Resistant Hypertension
    1. Seated Blood Pressure >140/90 mmHg despite adherance to 3 optimized Antihypertensives (e.g. ACE/ARB, hctz, CCB)
    2. Formal diagnosis assumes one Antihypertensive is a Thiazide Diuretic

IV. Indications: Combination Antihypertensive Therapy

  1. Failed Hypertension Monotherapy
  2. Hypertension

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
    1. Guidelines as of 2025 recommend starting a combination agent in Stage 2 Hypertension (>140/90)

VII. Causes: Resistant Hypertension

  1. Noncompliance with current regimen (pseudo-resistance, 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
    1. See BP Examination regarding pitfalls
    2. Example: BP cuff that is too small will artificially inflate Blood Pressure readings
  3. White coat Hypertension
    1. Perform Ambulatory Blood Pressure Monitoring
      1. 24 hour Ambulatory Blood Pressure Monitoring (preferred) OR
      2. Home Blood Pressure Monitoring twice daily for 5-7 days
    2. Increase regimen if average 24 hour BP >=130/80 or daytime average BP >=135/85
  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. Alcohol Use Disorder
      1. Common cause of Resistant Hypertension
      2. Husain (2014) World J Cardiol 6(5):245-52 +PMID: 24891935 [PubMed]
    4. 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. Consider Morning Aldosterone to Plasma Renin Activity (PRA) ratio
    5. 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
    6. 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. Medications: Newer Preferred Combinations

  1. Background
    1. Combinations are preferred for lowering cost and increasing compliance
    2. Angiotensin Receptor Blockers (ARB) are preferred over ACE Inhibitors
      1. Telmisartan (most potent, but fewer combinations available)
      2. Olmesartan (potent and many combinations)
      3. Valsartan (weaker, but many combinations)
    3. Thiazide Diuretics
      1. Chlorthalidone or Inapamide (potent, but fewer combinations, Hypokalemia is common)
      2. Hydrochlorothiazide (weakest, but most combinations)
    4. Amlodipine
      1. Amlodipine 5 mg orally daily is preferred dose (avoid 10 mg due to edema, without added benefit)
  2. ARB and Thiazide Combinations
    1. Olmesartan 20-40 mg AND Hydrochlorothiazide 12.5-25 mg
    2. Telmisartan 40-80 mg AND Hydrochlorothiazide 12.5-25 mg
    3. Irbesartan 150-300 mg AND Hydrochlorothiazide 12.5 mg
    4. Valsartan 80-160-320 mg AND Hydrochlorothiazide 12.5-25 mg (Diovan)
  3. ARB and Amlodipine
    1. Olmesartan 20-40 mg AND Amlodipine 5 mg
    2. Olmesartan 20-40 mg AND Hydrochlorothiazide 12.5-25 mg AND Amlodipine 5 mg
    3. Telmisartan 40-80 mg AND Amlodipine 5 mg
    4. Valsartan 160-320 mg AND Amlodipine 5 mg

IX. Medications: Older Combinations

  1. Prinizide (Lisinopril 10-20 mg with Hydrochlorothiazide 12.5-25 mg)
  2. Ziac (Bisoprolol with Hydrochlorothiazide 6.25)
  3. Lotrel (Benzapril 10-20 mg with Amlodipine 2.5-10 mg)
  4. Tarka (Trandolopril 1-2 mg with Verapamil 180-240 mg)
  5. Reserpine 1.25-2.5 mg with Hydrochlorothiazide 25 mg
  6. Tenoretic (Atenolol 50-100 mg with Chlorthalidone 25 mg)
    1. Other Beta Blockers are preferred

X. Protocol: Approach

  1. Consider reasons for Resistant Hypertension (e.g. Obstructive Sleep Apnea, see above)
  2. Optimize Medication Compliance and lifestyle interventions (e.g. Alcohol)
  3. Review Hypertension Risk Stratification
  4. Determine Hypertension Reduction Goal
    1. See Blood Pressure Goals in Hypertension
  5. Advance to next step if BP>15/10 above goal
  6. Antihypertensives are highly effective and best tolerated at 50% of maximum doses
    1. Maximizing medication doses to 100% increases adverse effects
    2. Adding another agent is far more effective than maximizing a single agents dose
    3. Wald (2009) Am J Med 122(3): 290-300 [PubMed]
  7. Consolidate medications into combination agents and once daily regimens
  8. Consider optimal strategies in specific populations when selecting medications
    1. See Hypertension Management for Specific Populations
  9. 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. Angiotensin Receptor Blocker (ARB, esp. Olmesartan, Telmisartan, Valsartan) AND
    2. Thiazide Diuretic
      1. Chlorthalidone or Inapamide are preferred as more potent and longer acting than Hydrochlorothiazide
        1. However more potent Thiazides are higher risk for Hypokalemia
  2. Serum Creatinine >1.5 to 1.8 mg/dl (or GFR <30 ml/min)
    1. Angiotensin Receptor Blocker AND
    2. Loop Diuretic
      1. Furosemide twice daily or Torsemide once daily
  3. Alternative
    1. ACE Inhibitors may be used instead of Angiotensin Receptor Blocker (ARB)
      1. However ARBs are now preferred over ACE Inhibitors (equivalent efficacy, fewer adverse effects)
    2. Do NOT combine ACE Inhibitor with Angiotensin Receptor Blocker

XII. Protocol: Step 2

  1. Dihydropyridine Calcium Channel Blocker (e.g. Amlodipine, Nifedipine)
    1. Amlodipine 5 mg orally daily
    2. Avoid increasing to 10 mg dose (minimal added benefit, associated with Leg Edema)

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, Atrial Fibrillation or other Beta Blocker specific indication)
    1. Add low dose Beta Blocker (e.g. Metoprolol)
    2. However, Beta Blockers are unlikely to substantially decrease resistant Blood Pressure
  3. Alternative
    1. Consider Combined alpha-beta adrenergic blocker instead of a Beta Blocker
      1. Carvedilol (or Labetalol)
    2. Consider Non-Dihydropyridine Calcium Channel Blocker
      1. Diltiazem (or Verapamil)

XIV. Protocol: Step 4

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

XV. Protocol: Step 5

  1. Consider Non-Dihydropyridine Calcium Channel Blocker (e.g. Diltiazem, Verapamil)
    1. Avoid combining with Beta Blocker in most cases
  2. Consider Endothelin Receptor Antagonist (e.g. Aprocitentan 12.5 mg daily)
  3. Consider Central Adrenergic Agonist (e.g. Clonidine, Guanfacine)
    1. Risk of sedation and Xerostomia
  4. Consider Hydralazine (Apresoline)
  5. Consider Reserpine (risk of Major Depression)
  6. 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

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. Haley (2026) Am Fam Physician 113(1): 43-50 [PubMed]
  5. James (2014) JAMA 311(5): 507-20 [PubMed]
  6. Moser (2006) N Engl J Med 355(4): 385-92 [PubMed]
  7. Viera (2009) Am Fam Physician 79(10): 863-9 [PubMed]

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