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A. Treatment Goals [27] navigator

  1. Key Recommendations from Joint National Committee on High Blood Pressure (BP) [1]
    1. In persons >50 years, systolic BP >140mm Hg is more important cardiovascular disease (CVD) risk factor than diastolic BP [29]
    2. Risk of CVD with BP >115/75 doubles with each increment of 20/10mm Hg
    3. Borderline HTN is defined as systolic BP 120-139 or diastolic BP 80-89
    4. Thiazide diuretics should be first line in ALL uncomplicated patients with HTN [4,19]
    5. Many or most patients with HTN will require 2 or more antihypertensive medications
    6. Goal BP: Nondiabetics: <140/90 mm Hg; diabetics or chronic kidney disease: <130/80
    7. Goal diastolic BP in patients with CAD >75-80mm Hg [84,85]
    8. If BP is >20/10mm Hg above goal BP, consider initiating therapy with 2 agents which should generally include a thiazide type diuretic
    9. Reduction of left ventricular hypertrophy (LVH) during anti-HTN therapy is associated with improved cardiovascular (CV) outcomes [16,17,33] including atrial fibrillation (AFib) [86]
    10. Physicians must motivate patients to take medications and alter lifestyle
  2. Adjuncts to Pharmacologic Therapy
    1. Diet modification will enhance the effects of antihypertensives
    2. Dietary counciling and lipid lowering is essential to reduce HTN and overall cardiac risks
    3. Low fat diet [57] or reduced sodium intake [55,58] or both improves BP [48,58]
    4. Diet modification plus drugs is particularly important in diabetes mellitus (DM) [2,59,73]
    5. Stopping smoking is also critical
    6. Moderate alcohol consumption
    7. Adequate potassium intake
    8. Particularly important in patients with additional CVD risks
  3. Combination Drug Therapy Often Required [1,4,58,69]
    1. Two or more drugs are often required for good BP control
    2. Lower dose combination of drugs is preferable to standard dose single drug therapy [9]
    3. Amlodipine ± perindopril superior to atenolol ± thiazide with respect to cardiovascular events and reduced risk of type 2 DM (DM2) [82,83]
  4. Slight and stable reductions in renal function with good HTN treatment are acceptable and recommended [68]
  5. Underlying causes of HTN should be evaluated and treated [1]
    1. Sleep Apnea
    2. Chronic renal disease
    3. Primary aldosteronism
    4. Renovascular disease
    5. Cushing Syndrome / Hypercortisolism (including iatrogenic)
    6. Coarctation of the aorta
    7. Thyroid or parathyroid disease
    8. Pheochromocytoma

B. Selection of Antihypertensive Agent [10,27] navigator

  1. Goals of Therapy
    1. Unless emergent, goals should be achieved relatively slowly
    2. Individualize per age, symptoms, other risk factors
    3. DBP should be lowered to <80-85mm; <80mm in DM [59]
    4. SBP should be lowered to <125mm or <140mm in elderly (>65 years) [18]
    5. Caution with significant BP reductions in elderly (>65 years) and in renovascular disease
    6. Caution with significant BP reduction in severe cerebrovascular disease
    7. Aspirin 75mg/d clearly reduces mortality when added to anti-HTN therapy [60]
    8. Most anti-HTN agents have similar efficacy and safety in large meta-analyses [4,24,44,61]
    9. In >55 year olds with HTN and at least 1 other CVD risk factor, chlorthalidone was superior to amlodipine or lisinopril at reducing overall CVD events but not all mortality [5]
    10. More than one agent is usually required to achieve BP goals [1]
    11. If BP is >20/10mm Hg above goal BP, consider initiating therapy with 2 agents which should generally include a thiazide type diuretic [1,3]
    12. Treatment of "pre-HTN" with candesartan, an angiotensin receptor blocker (ARB), reduced development of frank HTN by 15% over 4 years with side effects similar to placebo [8]
    13. alpha-adrenergic blockers should be reserved for 3rd-4th line [42,61,65]
  2. Primary Agent Class [5,6,7,10]
    1. Choice of agent is dependent primarily on comorbid conditions (see below) [29]
    2. Diuretic recommended for 1st line in most patients [19,29]
    3. Thiazide diuretics (12.5-25mg chlorthalidone or hydrochlorothiazide, HCTZ) preferred 1st line overall [3,4,5,6,19] except in men >65 years, where ACE-I preferred [72]
    4. In persons >80 years old with HTN, indapamide (Lozol®) sustained release ± perindopril reduced all-cause mortality, CVD realed-death, and CHF [23]
    5. Low-dose diuretics have been most effective first line therapy for preventing CVD mortality, morbidity in both blacks and non-blacks and in elderly [3,4,19,23]
    6. Diuretics had best overall outcomes in women 50-79 years old as monotherapy [81]
    7. ARB and ACE-I have lowest incidence of new onset DM2, placebo and calcium channel blockers (CCB) next; ß-blockers and diuretics highest rates [22]
    8. Except for patients with documented cardiac ischemia or coronary artery disease (CAD), ß-adrenergic blockers are not first line [28]
    9. In blacks, CCB are most effective; ACE-I alone or ß-blockers are least effective [79]
    10. ARB or ACE-I or verapamil for LVH [16,35,67,86]
    11. Certain CCB not first line due to some increased CV events, but not overall mortality, compared with other types of agents [24,46]
    12. Long acting CCB have reduced CV events and mortality and clearly reduce stroke events but can increase CHF risk [4,11,24]
    13. CCB were inferior monotherapy to ACE-I, ß-blockers, thiazides in women 50-79 years [81]
    14. Amlodipine, a CCB, has better initial BP reduction than valsartan (an ARB) and similar protection on CV outcomes; valsartan reduces incidence of new onset DM [78]
    15. Amlodipine ± perindopril superior to atenolol ± thiazide with respect to cardiovascular events and reduced risk of DM2 [82,83]
    16. Verapamil, a CCB, with trandolapril (ACE-I) was as effective and safe as atenolol (ß-blocker) with a diuretic [13]
    17. Atenolol alone has questionable efficacy as an antihypertensive [80] and appears to increase the risk of DM2 [83]
    18. alpha-1 adrenergic blockers are no longer recommended first line due to increased CV events [42,61]
    19. Overall mortality may not be improved by ß-blockers or HIGH dose diuretics [42]
    20. Low dose diuretics clearly reduce morbidity and mortality [3,5]
    21. Lower doses of two agents have similar effeicacy in BP reduction but reduced adverse effects [9]
  3. Primary Agent Failure [10]
    1. Add second drug, or increase 1st drug, or substitute drugs
    2. Thiazide diuretic should be used in most HTN patients [1,3,5,10,81]
    3. Amlodipine ± perindopril superior to atenolol ± thiazide with respect to cardiovascular events and reduced risk of DM2 [82,83]
    4. Add third drug or increase the second drug
    5. A secondary cause of HTN should be sought if >3 drugs required for BP control
    6. Add fourth drug, change drug combination
    7. Consider low dose drug combinations (such as Ziac®) [9]
  4. Selected Comorbid Conditions [10,59,61]
    1. ACE-I and ARB have similar efficacy in essential HTN; ARB have reduced cough [90]
    2. ACE-I or ARB ALWAYS first line in DM [43,59,73,74,91]
    3. ACE-I or ARB preferable in early or moderate [53] or advanced [89] renal failure
    4. ACE-I or ARB protective against HTN induced renal failure versus ß-blockers and CCB [70]
    5. ACE-I or ARB are first line in congestive heart failure (CHF) with or without HTN
    6. ACE-I or ARB are most effective in patients with LVH and HTN [67,86]
    7. ACE-I ramipril reduced total and CV mortality in high risk patients [14]
    8. In persons >60 years, low dose thiazides reduce BP and stroke risk
    9. Low dose diuretics reduce CVD and total mortality and had best overall profile in persons >55 years old with HTN + an additional CVD risk factor [5]
    10. Carvidilol, a non-selective adrenergic blocker anti-oxidant, indicated for CHF and HTN
    11. Patients with benign prostatic hypertrophy with HTN may benefit from adding alpha1- adrenergic blockers (but these should not be first line)
    12. Long acting CCB may be best at reducing stroke risk [24]
    13. Long acting CCB are likely inferior to other drugs for reducing MI and CHF risk [11]
  5. Risk for Cardiac Arrest (sudden cardiac death)
    1. High or moderate dose diuretics increased risk for arrest, probably due to hypokalemia
    2. Addition of K+ sparing agent decreased this risk
    3. Low dose diuretics (such as HCTZ 12.5mg qd) do not appear to reduce potassium
    4. ß-blockers are probably most effective for preventing sudden cardiac death
  6. Other Side Effects
    1. Both ß-blockers and diuretics increase total cholesterol and decrease HDL levels
    2. Diuretics and ß-blockers can worsen insulin resistance, cause hyperinsulinemia
    3. Non-selective ß-blockers had slightly higher hypoglycemic attacks than other drugs
    4. Doxazosin, an alpha1-blocker, increased CV events versus diuretics (chlorthalidone) even when other agents were added to it [42,65]
    5. BP reduction can lead to reduced renal perfusion and slight worsening of renal function tests [68]
    6. However, stable reduction in renal function is acceptable with improved BP control
    7. Long term control of BP will lead to improved preservation of renal function [68]
  7. Treatment in Pregnancy [88]

C. Summary of Anti-Hypertensive Agents [7,50] navigator

  1. Thiazides and Related Diuretics [3,5,6]
    1. Very effective in elderly with isolated systolic HTN for stroke reduction
    2. Low dose diuretics (12.5-25mg po qd chlorthalidone or HCTZ) reduce heart failure, stroke, CVD and overall death rates [3,5,30]
    3. In persons >80 years old with HTN, indapamide (Lozol®) sustained release ± perindopril reduced all-cause mortality, CVD realed-death, and CHF [23]
    4. Do not appear to increase the risk for development of DM [41]
    5. May cause or exacerbate hyperlipidemia
    6. Very inexpensive
    7. Higher dose thiazides likely increase cardiac death
    8. The increased risk of sudden cardiac death may be due to hypokalemia / hypomagnesemia
    9. Use of thiazides and other diuretics should include electrolyte monitoring
    10. Low dose thiazides with electrolyte monitoring should be considered first line unless patients have DM
  2. ACE-I [47]
    1. ACE-I are very effective and preferred in many settings except alone in blacks [79]
    2. Addition of a diuretic to ACE-I improves efficacy in black and resistant patients
    3. ACE-I (or ARB) are first line in ALL patients with DM (types 1 or 2) [2,22,43,59]
    4. ACE-I confer benefits in diabetics that are independent of BP effects [51]
    5. ACE-I safe in chronic obstructive pulmonary disease, CHF, peripheral vascular disease
    6. Caution in renal insufficiency with serum creatinine > 2.5mg/dL
    7. Fosinopril is 50% hepatically cleared and may be safer than other ACE-I in renal failure
    8. In renal insufficiency with proteinuria, ramipril reduces renal decline better than amlodipine [53]
    9. ACE-I may halt or slow decline of muscle strength in women with HTN age >70 [62]
    10. Combination ACE-I with Ca2+ blockers or diuretics, other agents, are available
  3. ARB [66]
    1. As effective for HTN as ACE-I and better tolerated (much reduced cough)
    2. Confers clinical benefits beyond reduction in BP [63,64]
    3. Losartan reduces CV mortality and death more than atenolol in 55-80 year olds with or without DM or LVH and is better tolerated [63,64,67]
    4. Losartan reduced CV morbidity, stroke and death more than atenolol, independent of BP control, in 55-80 year olds without clinically evident vascular disease [32]
    5. Efficacy of ARB is increased with thiazide diuretic (such as HCTZ) added
    6. BP reduction slightly less than amlodipine but similar protection on CV outcomes [78]
    7. ARBs reduce risk of new development of DM compared with CCBs [78], diuretics and ß-blockers [22]
    8. ARB no better than standard therapy in treatment of patients with HTN and diastolic dysfunction [87]
  4. ß-Adrenergic Blockers [49]
    1. Generally not considered first line with overall increased risk of stroke [28] or DM2 [22]
    2. Should be used early in all patients with myocardial ischemia, MI, some arrhythmias
    3. Contraindicated in COPD, bradycardia, sick sinus syndrome
    4. Use any ß-blocker with care in the elderly who often have conduction system disease
    5. Less effective in blacks, but addition of diuretic often provides good results [79]
    6. Prevents reflex tachycardia when added to vasodilating Ca blocker or direct vasodilator
    7. Typical ß-blockers should be used with caution in diabetics unless post-MI
    8. ß-adrenergic blockers may increase risk of developing DM; this should be balanced against positive cardiac effects [41]
    9. ß-blockers with intrinsic sympathomimetic activity (ISA) may be used in patients who have conduction system disease, baseline bradycardia, or drug-related bradycardia
    10. ß-Blocker doses must be increased cautiously in patients with CHF
    11. Carvidilol uniquely improves glucose control and lipid metabolism in diabetics
    12. Labetolol is a mixed ß-blocker and alpha1-adrenergic blocker which is very potent
    13. In HTN patients with panic disorder or migraine, ß-blockers may be preferred
    14. Cardioselective agents do not adversely affect patients with asthma or other hyperactive airways disease [71]
    15. ß-blockers provide poor reduction in LV mass in LVH [35] but reduce AFib incidence [86]
  5. Calcium Channel Blockers (CCB) [11,12,31,47]
    1. Current agents are specific for L-type (long acting) calcium channels
    2. Long acting (once daily) CCB are effective and well tolerated
    3. Short acting CCB should not be used
    4. CCB are probably second line due to increased risk of CHF [11,12,46]
    5. For HTN with LVH, consider agents with anti-inotropic activity (verapamil, diltiazem)
    6. LVH: Verapamil superior to ß- blocker for reduction in LV mass
    7. Verapamil with ACE-I as effective and safe as ß-blocker with diuretic [13]
    8. Verapamil (controlled onset) neither superior nor inferior to diuretics or ß-blockers for initial treatment of HTN [76]
    9. Verapamil is safe but not superior to other agents for HTN treatment
    10. Diltiazem appears most effective in black patients (see above)
    11. Amlodipine (Norvasc®) generally safe, good BP reduction, easily combined
    12. Felodipine (Plendil®) 5mg/d well tolerated and clearly reduces HTN related mortality
    13. Diltiazem, ß-blockers and diuretics had similar effects on overall vascular mortility [44]
    14. Unclear if dihydropyridine CCB are detrimental in diabetics with HTN [43]
    15. Overall, CCB are safe and effective in DM with HTN, slight increase in CHF risk [11,12]
    16. Nisoldipine had ~10X increased risk of heart attacks in DM versus enalapril
    17. Nitrendipine safe and effective in elderly DM with systolic HTN [34]
    18. Long acting nifedipine as good as combination diuretic in reducing vascular mortality [45]
    19. Caduet® is amlopidine (Plendil®) in combination with atorvastatin (Lipitor®) [15]
  6. alpha1-Adrenergic Blockers
    1. Improve BP effectively as well as most of the common comorbidities
    2. Increased risk of CV events (CHF) compared with low dose diuretic makes these agents 3rd line monotherapy or use only in combinations [42,61,65]
    3. Prazosin is short acting agent and may cause syncopal events, particularly in elderly
    4. Longer acting agents (doxazosin, terazosin) are well tolerated when titrated
    5. Longer acting agents do not appear to induce tachyphylaxis and orthostasis
    6. Improve urinary symptoms in men with prostatic hyperplasia
  7. alpha2-Adrenergic Agonists
    1. Inhibit sympathetic outflow from Central Nervous System (CNS)
    2. Reduce blood pressure through vasodilation; little reduction in heart rate
    3. Clonidine is the most commonly used agent
    4. Monoxodine is also under development
  8. Direct Vasodilators
    1. Potent agents that cause marked reflex tachycardia
    2. Minoxidil and hydralazine are the major agents
    3. Should be used only in combination with a ß-blocker or verapamil or diltiazem
    4. Hydralazine - 40-200mg per day divided bid-qid
    5. Minoxidil - 2.5-40mg per day divided qd or bid (very potent agent)
    6. Caution with use of these agents which may exacerbate angina, other side effects
  9. Renin Inhibitor [25,26]
    1. Aliskiren (Tekturna®) is orally available, non-peptide selective renin inhibitor now approved
    2. Inhibition in first step in production of angiotensin
    3. Blood pressure reduction similar to ACE-I and ARB
    4. Do not affect degradation of BK
    5. May be particularly useful in combination with drugs that lead to reactive increase in renin including ACE-I, ARB, diuretics
    6. Combined aliskiren+valsartan reduces diastolic BP 12.2mm versus 9-10mm with either drug alone, versus 4mm with placebo [21]
    7. Do not cause angioedema
    8. Aliskiren dose is 150mg qd initially, then up to 300mg po qd
    9. Good synergy with diuretics and ARB
  10. Endothelin Receptor Antagonist
    1. Bosentan (Tracleer®) is an orally active, mixed ETa/ETb receptor antagonist [36]
    2. Administration of 100-2000mg/day reduces blood pressure (~12mm max)
    3. Bosentan increased plasma endothelin, mild reduction in angiotensin II
    4. As effective as enalapril in systemic HTN but ~20% develop liver function abnormalities
    5. Approved for pulmonary HTN
    6. Bosentan caused headache, flushing, leg edema, transaminase increases
    7. Darusentan reduces BP in patients wtih CHF but no effect on CHF symptoms [20]
  11. Aldosterone Blockade [77]
    1. Potassium sparing diuretics which block aldosterone receptors
    2. Moderate antihypertensive activity
    3. Effective in severe CHF
    4. Spironolactone (Aldactone®): 25mg po bid-tid initially (likely can be given qd; max 450mg/d)
    5. Eplerenone (Inspra®): 50mg po qd to start, up to 100mg po bid
    6. Main risk is hyperkalemia; monitoring is required
    7. Spironolactone has higher risk of gynecomastia than eplerenone
    8. Impotence and menstrual disturbances are uncommon with both agents
  12. Combination agents are available for most drug classes and have added efficacy

D. Effects of Anti-Hypertensive Therapy on Comorbid Conditionsnavigator

  1. JNC-VII strongly recommende drug choices be made based on comorbid conditions [1]
  2. Adequate control of HTN is critical, particularly to slow progression of comorbid diseases
  3. Age, ethnicity, and to some extent renin profile, are considered in selecting agent [39]
  4. DM2
    1. ACE-I or ARB are ALWAYS the preferred agents
    2. ARBs for any ACE-I intolerant patients unless angioedema has occurred [4]
    3. DM2 incidence is lowest in HTN patients treated with ARB or ACE-I compared with other agents [22]
    4. alpha1-blockers improve metabolic profiles but may increase risk for CHF
    5. ß-blockers should be used with caution
  5. Hyperlipidemia [37,38]
    1. Thiazides and related agents increased cholesterol levels (effect may wane at 2 years)
    2. ß-blockers raised triglycerides slightly
    3. ß-blockers with intrinsic sympathomimetic activity lowered total cholesterol levels
    4. ACE-I lowered triglycerides and in diabetics, reduced total cholesterol levels
    5. Vasodilators excluding CCB lowered total cholesterol
    6. CCBs had no effect on cholesterol
    7. alpha1-blockers lowered cholesterol and raised HDL more than any other agent but are generally reserved for 3rd or 4th line due to increased CVD events
  6. Treatment with atorvastatin (Lipitor®) in patients with HTN and average or low cholesterol levels reduces stroke and CV events ~30% [75]

E. Table: Antihypertensive Agents and Comorbid Conditionsnavigator
Group:Thiazidesß-BlockersACE-IARBCCBa1-Blockera2-Agonist
Diabetes----*+++++/-+--
Hyperlipidemia±+/-±+--+++
CHF±+/-*+++++--++
LVH--+++++++----
Bradycardia+--+++++/-+--
Post-MI--+++++++---+--
Elderly++++/-++++++/---
Blacks±+/-+/-+++++
*Carvidolol improves glucose and lipid control in diabetics and is indicated for CHF [40]
ß-adrenergic blockers may increase risk of developing DM, but thiazides do not [41]
Low dose thiazide diuretics are recommended first line in most patients [1,6]
ARB can usually be used in ACE-I intolerant patients and are likely equivalent

Resources navigator

calcMean Arterial Pressure (MAP)

References navigator

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