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

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

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

XII. Protocol: Step 2

  1. Add Non-Dihydropyridine Calcium Channel Blocker (e.g. Diltiazem, Verapamil)
    1. Alternatively, consider Dihydropyridine Calcium Channel Blocker (e.g. Amlodipine, Nifedipine)

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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Related Studies

Ontology: Antihypertensive Agents (C0003364)

Definition (MEDLINEPLUS)

High blood pressure, also called hypertension, usually has no symptoms. But it can cause serious problems such as stroke, heart failure, heart attack and kidney failure. If you cannot control your high blood pressure through lifestyle changes such as losing weight and reducing sodium in your diet, you may need medicines.

Blood pressure medicines work in different ways to lower blood pressure. Some remove extra fluid and salt from the body. Others slow down the heartbeat or relax and widen blood vessels. Often, two or more medicines work better than one.

NIH: National Heart, Lung, and Blood Institute
Definition (NCI) Any substance used in the treatment of acute or chronic hypertension regardless of pharmacological mechanism. Antihypertensive agents include diuretics, alpha-adrenergic and beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, ganglionic blockers, and vasodilator agents.
Definition (CSP) agent that reduces high blood pressure.
Definition (MSH) Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.
Concepts Pharmacologic Substance (T121)
MSH D000959
SnomedCT 1182007, 372586001
LNC LP31453-1
English Agents, Antihypertensive, antihypertensive agent, Antihypertensive Drugs, Agents, Anti-Hypertensive, Anti Hypertensive Agents, Anti Hypertensive Drugs, Anti Hypertensives, Anti-Hypertensive Agents, Anti-Hypertensive Drugs, Anti-Hypertensives, Antihypertensives, Drugs, Anti-Hypertensive, Drugs, Antihypertensive, antihypertensives (medication), antihypertensives, anti hypertensive, antihypertensives drugs, anti hypertensive drug, anti-hypertensive drugs, hypotensive agent, antihypertensive drug, antihypertensive drugs, anti hypertensives, antihypertensive, antihypertensive agents, hypotensive agents, anti-hypertensives, anti hypertensive drugs, blood pressure lowering drug, Antihypertensive Agents, Antihypertensive medicines, Antihypertensive Medicines, High Blood Pressure Medicines, High blood pressure medicines, Blood Pressure Medicines, ANTIHYPERTENSIVES, Hypotensive agents, Antihypertensive drug, Antihypertensive, Hypotensive agent (product), Hypotensive agent (substance), Hypotensive agent, Antihypertensive agent, Antihypertensive agent, NOS, Antihypertensive drug, NOS, Hypotensive agent, NOS, Hypotensive Agents, Hypotensive Drugs, Hypotensives, Antihypertensive Agent
French Agents antihypertenseurs, Médicaments antihypertenseurs, Anti-hypertenseurs, Antihypertenseurs
Swedish Blodtryckssänkande medel
Czech hypotenzíva, antihypertenzíva, hypotonika
Finnish Verenpainelääkkeet
Italian Farmaci antiipertensivi, Antiipertensivi
Russian GIPOTENZIVNYE SREDSTVA, ANTIGIPERTENZIVNYE SREDSTVA, АНТИГИПЕРТЕНЗИВНЫЕ СРЕДСТВА, ГИПОТЕНЗИВНЫЕ СРЕДСТВА
Croatian ANTIHIPERTENZIVI
Polish Leki obniżające ciśnienie, Leki hipotensyjne, Leki przeciwnadciśnieniowe
Japanese 血圧下降剤, 降圧剤, 抗高血圧症薬, 抗高血圧薬, 血圧降下剤, 血圧降下薬, 降圧物質, 降圧薬
Spanish Antihipertensivos, Fármacos Antihipertensivos, Agentes Antihipertensivos, agente antihipertensivo, agente hipotensor (producto), agente hipotensor (sustancia), agente hipotensor, droga antihipertensiva
Norwegian Blodtrykkssenkende midler
Portuguese Agentes Anti-Hipertensivos, Fármacos Anti-Hipertensivos, Anti-Hipertensivos
German Antihypertonika, Blutdrucksenkende Mittel, Antihypertensiva
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Hypertensive disease (C0020538)

Definition (MEDLINEPLUS)

Blood pressure is the force of your blood pushing against the walls of your arteries. Each time your heart beats, it pumps out blood into the arteries. Your blood pressure is highest when your heart beats, pumping the blood. This is called systolic pressure. When your heart is at rest, between beats, your blood pressure falls. This is the diastolic pressure.

Your blood pressure reading uses these two numbers, the systolic and diastolic pressures. Usually they are written one above or before the other. A reading of

  • 119/79 or lower is normal blood pressure
  • 140/90 or higher is high blood pressure
  • Between 120 and 139 for the top number, or between 80 and 89 for the bottom number is prehypertension

High blood pressure usually has no symptoms, but it can cause serious problems such as stroke, heart failure, heart attack and kidney failure. You can control high blood pressure through healthy lifestyle habits and taking medicines, if needed.

NIH: National Heart, Lung, and Blood Institute
Definition (NCI_CDISC) Pathological increase in blood pressure defined as one of the following: History of hypertension diagnosed and treated with medication, diet, and/or exercise; On at least 2 separate occasions, documented blood pressure greater than 140 mm Hg systolic and/or 90 mm Hg diastolic in patients without diabetes or chronic kidney disease, or blood pressure greater than 130 mm Hg systolic or 80 mm Hg diastolic in patients with diabetes or chronic kidney disease; Currently on pharmacological therapy for the treatment of hypertension.
Definition (NCI) Blood pressure that is abnormally high.
Definition (NCI_CTCAE) A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg.
Definition (NCI_NCI-GLOSS) A blood pressure of 140/90 or higher. High blood pressure usually has no symptoms. It can harm the arteries and cause an increase in the risk of stroke, heart attack, kidney failure, and blindness.
Definition (CSP) persistantly high arterial blood pressure.
Definition (MSH) Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.
Concepts Disease or Syndrome (T047)
MSH D006973
ICD9 997.91, 401-405.99
ICD10 I10-I15.9 , I10, I10-I15
SnomedCT 38341003, 155302005, 194757006, 194760004, 155295004, 194756002, 266287006, 194794002, 195537001
LNC MTHU020789, LA14293-7, LA7444-8
English Hypertension, BLOOD PRESSURE HIGH, HYPERTENSION ARTERIAL, Hypertensive disease NOS, Hypertensive diseases, [X]Hypertensive diseases, Systemic hypertension, Hypertensive disorder, systemic arterial, hyperpiesia, hyperpiesis, systemic HTN, systemic hypertension (diagnosis), systemic hypertension, Hypertension arterial, Blood pressure high, HBP, HT, Hypertension NOS, Surg comp - hypertension, HTN, Hypertension [Disease/Finding], high blood pressure, hypertensive disorder, hypertensive vascular disease, arterial hypertension, arterial hypertension systemic, vascular hypertension, blood high pressure, high blood pressure disorder, systemic arterial hypertension, hypertensive disease, Hypertensive diseases (I10-I15), Complications affecting other specified body systems, not elsewhere classified, hypertension, High Blood Pressure, Hypertensive disease NOS (disorder), Hypertensive disease (disorder), (Hypertensive disease) or (hypertension), (Hypertensive disease) or (hypertension) (disorder), [X]Hypertensive diseases (disorder), hypertension, BLOOD PRESSURE, INCREASED, BLOOD PRESSURE, HIGH, Hypertensive Disorder, HIGH BLOOD PRESSURE, INCREASED BLOOD PRESSURE, HYPERTENSION, PRESSURE, HIGH BLOOD, High blood pressure, Hyperpiesia, Hyperpiesis, Hypertensive vascular degeneration, Hypertensive vascular disease, BP - High blood pressure, High blood pressure disorder, Systemic arterial hypertension, HBP - High blood pressure, BP+ - Hypertension, HT - Hypertension, Hypertensive disorder, systemic arterial (disorder), Hypertensive disorder, HTN - Hypertension, blood pressure; high, high; arterial tension, high; blood pressure, Hypertension, NOS, Hypertensive disease, NOS, Raised blood pressure (disorder), Blood Pressure, High, Blood Pressures, High, High Blood Pressures, Vascular Hypertensive Disorder, Hypertensive disease, HYPERTENSIVE DISEASE
French HYPERTENSION ARTERIELLE, Pression artérielle élevée, PAH, Hypertension SAI, TH, HYPERTENSION, TENSION ARTERIELLE E, Hypertension chronique, Hypertension permanente, Hypertension artérielle, Hypertension
Portuguese HIPERTENSAO, Hipertensão arterial NE, Hipertensão arterial, Pressão arterial alta, HYPERTENSAO ARTERIAL, PRESSAO SANGUINEA ELEVADA, Pressão Arterial Alta, Pressão Sanguínea Alta, Hipertensão
Spanish HIPERTENSION, PRESION SANGUINEA ALTA, Presión sanguínea alta, HTA, Hipertensión NEOM, Hipertensión arterial, HT, HIPERTENSION ARTERIAL, enfermedad hipertensiva, SAI, [X]enfermedades hipertensivas (trastorno), enfermedad hipertensiva, SAI (trastorno), [X]enfermedades hipertensivas, Hypertensive disease NOS, degeneración vascular hipertensiva, enfermedad hipertensiva, enfermedad vascular hipertensiva, hiperpiesia, hiperpiesis, hipertensión arterial (trastorno), hipertensión arterial, presión arterial alta, tensión arterial alta, tensión arterial elevada, Hipertensión, Presión Sanguínea Alta
German HYPERTONIE, Hypertonie, arteriell, Blutdruck, hoch, HBP, HT, Hypertonie NNB, BLUTDRUCK HOCH, HYPERTONIE ARTERIELL, Hypertension, Hypertonie
Dutch hypertensie NAO, hoge bloeddruk, arteriële hypertensie, bloeddruk; hoog, hoog; arteriële druk, hoog; bloeddruk, hypertensie, Bloeddruk, hoge, Hypertensie
Italian Ipertensione (HT), Ipertensione NAS, Pressione del sangue elevata, Ipertensione, Pressione sanguigna alta, Ipertensione arteriosa
Japanese 動脈性高血圧, 高血圧ＮＯＳ, ｺｳｹﾂｱﾂ, ｺｳｹﾂｱﾂNOS, ﾄﾞｳﾐｬｸｾｲｺｳｹﾂｱﾂ, 高血圧, 高血圧症
Swedish Högt blodtryck
Czech hypertenze, Arteriální hypertenze, Vysoký krevní tlak, Hypertenze NOS, Hypertenze, vysoký krevní tlak, hypertonie
Finnish Kohonnut verenpaine
Russian GIPERTENZIIA, GIPERTONICHESKAIA BOLEZN', KROVIANOE DAVLENIE VYSOKOE, ГИПЕРТЕНЗИЯ, ГИПЕРТОНИЧЕСКАЯ БОЛЕЗНЬ, КРОВЯНОЕ ДАВЛЕНИЕ ВЫСОКОЕ
Croatian HIPERTENZIJA
Polish Nadciśnienie
Hungarian Arteriás hypertonia, Hypertensio, HT, RR magas, Hypertonia k.m.n., Magas vérnyomás
Norwegian Høyt blodtrykk, Hypertensjon, Hypertoni
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: ANTIHYPERTENSIVE COMBINATIONS (C1874305)

Concepts Pharmacologic Substance (T121)
English ANTIHYPERTENSIVE COMBINATIONS, antihypertensive combinations (medication), antihypertensive combinations, [CV400] ANTIHYPERTENSIVE COMBINATIONS
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Hypertension

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