A. Treatment Goals [27]
- Key Recommendations from Joint National Committee on High Blood Pressure (BP) [1]
- In persons >50 years, systolic BP >140mm Hg is more important cardiovascular disease (CVD) risk factor than diastolic BP [29]
- Risk of CVD with BP >115/75 doubles with each increment of 20/10mm Hg
- Borderline HTN is defined as systolic BP 120-139 or diastolic BP 80-89
- Thiazide diuretics should be first line in ALL uncomplicated patients with HTN [4,19]
- Many or most patients with HTN will require 2 or more antihypertensive medications
- Goal BP: Nondiabetics: <140/90 mm Hg; diabetics or chronic kidney disease: <130/80
- Goal diastolic BP in patients with CAD >75-80mm Hg [84,85]
- If BP is >20/10mm Hg above goal BP, consider initiating therapy with 2 agents which should generally include a thiazide type diuretic
- 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]
- Physicians must motivate patients to take medications and alter lifestyle
- Adjuncts to Pharmacologic Therapy
- Diet modification will enhance the effects of antihypertensives
- Dietary counciling and lipid lowering is essential to reduce HTN and overall cardiac risks
- Low fat diet [57] or reduced sodium intake [55,58] or both improves BP [48,58]
- Diet modification plus drugs is particularly important in diabetes mellitus (DM) [2,59,73]
- Stopping smoking is also critical
- Moderate alcohol consumption
- Adequate potassium intake
- Particularly important in patients with additional CVD risks
- Combination Drug Therapy Often Required [1,4,58,69]
- Two or more drugs are often required for good BP control
- Lower dose combination of drugs is preferable to standard dose single drug therapy [9]
- Amlodipine ± perindopril superior to atenolol ± thiazide with respect to cardiovascular events and reduced risk of type 2 DM (DM2) [82,83]
- Slight and stable reductions in renal function with good HTN treatment are acceptable and recommended [68]
- Underlying causes of HTN should be evaluated and treated [1]
- Sleep Apnea
- Chronic renal disease
- Primary aldosteronism
- Renovascular disease
- Cushing Syndrome / Hypercortisolism (including iatrogenic)
- Coarctation of the aorta
- Thyroid or parathyroid disease
- Pheochromocytoma
B. Selection of Antihypertensive Agent [10,27]
- Goals of Therapy
- Unless emergent, goals should be achieved relatively slowly
- Individualize per age, symptoms, other risk factors
- DBP should be lowered to <80-85mm; <80mm in DM [59]
- SBP should be lowered to <125mm or <140mm in elderly (>65 years) [18]
- Caution with significant BP reductions in elderly (>65 years) and in renovascular disease
- Caution with significant BP reduction in severe cerebrovascular disease
- Aspirin 75mg/d clearly reduces mortality when added to anti-HTN therapy [60]
- Most anti-HTN agents have similar efficacy and safety in large meta-analyses [4,24,44,61]
- 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]
- More than one agent is usually required to achieve BP goals [1]
- 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]
- 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]
- alpha-adrenergic blockers should be reserved for 3rd-4th line [42,61,65]
- Primary Agent Class [5,6,7,10]
- Choice of agent is dependent primarily on comorbid conditions (see below) [29]
- Diuretic recommended for 1st line in most patients [19,29]
- 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]
- In persons >80 years old with HTN, indapamide (Lozol®) sustained release ± perindopril reduced all-cause mortality, CVD realed-death, and CHF [23]
- 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]
- Diuretics had best overall outcomes in women 50-79 years old as monotherapy [81]
- 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]
- Except for patients with documented cardiac ischemia or coronary artery disease (CAD), ß-adrenergic blockers are not first line [28]
- In blacks, CCB are most effective; ACE-I alone or ß-blockers are least effective [79]
- ARB or ACE-I or verapamil for LVH [16,35,67,86]
- Certain CCB not first line due to some increased CV events, but not overall mortality, compared with other types of agents [24,46]
- Long acting CCB have reduced CV events and mortality and clearly reduce stroke events but can increase CHF risk [4,11,24]
- CCB were inferior monotherapy to ACE-I, ß-blockers, thiazides in women 50-79 years [81]
- 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]
- Amlodipine ± perindopril superior to atenolol ± thiazide with respect to cardiovascular events and reduced risk of DM2 [82,83]
- Verapamil, a CCB, with trandolapril (ACE-I) was as effective and safe as atenolol (ß-blocker) with a diuretic [13]
- Atenolol alone has questionable efficacy as an antihypertensive [80] and appears to increase the risk of DM2 [83]
- alpha-1 adrenergic blockers are no longer recommended first line due to increased CV events [42,61]
- Overall mortality may not be improved by ß-blockers or HIGH dose diuretics [42]
- Low dose diuretics clearly reduce morbidity and mortality [3,5]
- Lower doses of two agents have similar effeicacy in BP reduction but reduced adverse effects [9]
- Primary Agent Failure [10]
- Add second drug, or increase 1st drug, or substitute drugs
- Thiazide diuretic should be used in most HTN patients [1,3,5,10,81]
- Amlodipine ± perindopril superior to atenolol ± thiazide with respect to cardiovascular events and reduced risk of DM2 [82,83]
- Add third drug or increase the second drug
- A secondary cause of HTN should be sought if >3 drugs required for BP control
- Add fourth drug, change drug combination
- Consider low dose drug combinations (such as Ziac®) [9]
- Selected Comorbid Conditions [10,59,61]
- ACE-I and ARB have similar efficacy in essential HTN; ARB have reduced cough [90]
- ACE-I or ARB ALWAYS first line in DM [43,59,73,74,91]
- ACE-I or ARB preferable in early or moderate [53] or advanced [89] renal failure
- ACE-I or ARB protective against HTN induced renal failure versus ß-blockers and CCB [70]
- ACE-I or ARB are first line in congestive heart failure (CHF) with or without HTN
- ACE-I or ARB are most effective in patients with LVH and HTN [67,86]
- ACE-I ramipril reduced total and CV mortality in high risk patients [14]
- In persons >60 years, low dose thiazides reduce BP and stroke risk
- 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]
- Carvidilol, a non-selective adrenergic blocker anti-oxidant, indicated for CHF and HTN
- Patients with benign prostatic hypertrophy with HTN may benefit from adding alpha1- adrenergic blockers (but these should not be first line)
- Long acting CCB may be best at reducing stroke risk [24]
- Long acting CCB are likely inferior to other drugs for reducing MI and CHF risk [11]
- Risk for Cardiac Arrest (sudden cardiac death)
- High or moderate dose diuretics increased risk for arrest, probably due to hypokalemia
- Addition of K+ sparing agent decreased this risk
- Low dose diuretics (such as HCTZ 12.5mg qd) do not appear to reduce potassium
- ß-blockers are probably most effective for preventing sudden cardiac death
- Other Side Effects
- Both ß-blockers and diuretics increase total cholesterol and decrease HDL levels
- Diuretics and ß-blockers can worsen insulin resistance, cause hyperinsulinemia
- Non-selective ß-blockers had slightly higher hypoglycemic attacks than other drugs
- Doxazosin, an alpha1-blocker, increased CV events versus diuretics (chlorthalidone) even when other agents were added to it [42,65]
- BP reduction can lead to reduced renal perfusion and slight worsening of renal function tests [68]
- However, stable reduction in renal function is acceptable with improved BP control
- Long term control of BP will lead to improved preservation of renal function [68]
- Treatment in Pregnancy [88]
C. Summary of Anti-Hypertensive Agents [7,50]
- Thiazides and Related Diuretics [3,5,6]
- Very effective in elderly with isolated systolic HTN for stroke reduction
- Low dose diuretics (12.5-25mg po qd chlorthalidone or HCTZ) reduce heart failure, stroke, CVD and overall death rates [3,5,30]
- In persons >80 years old with HTN, indapamide (Lozol®) sustained release ± perindopril reduced all-cause mortality, CVD realed-death, and CHF [23]
- Do not appear to increase the risk for development of DM [41]
- May cause or exacerbate hyperlipidemia
- Very inexpensive
- Higher dose thiazides likely increase cardiac death
- The increased risk of sudden cardiac death may be due to hypokalemia / hypomagnesemia
- Use of thiazides and other diuretics should include electrolyte monitoring
- Low dose thiazides with electrolyte monitoring should be considered first line unless patients have DM
- ACE-I [47]
- ACE-I are very effective and preferred in many settings except alone in blacks [79]
- Addition of a diuretic to ACE-I improves efficacy in black and resistant patients
- ACE-I (or ARB) are first line in ALL patients with DM (types 1 or 2) [2,22,43,59]
- ACE-I confer benefits in diabetics that are independent of BP effects [51]
- ACE-I safe in chronic obstructive pulmonary disease, CHF, peripheral vascular disease
- Caution in renal insufficiency with serum creatinine > 2.5mg/dL
- Fosinopril is 50% hepatically cleared and may be safer than other ACE-I in renal failure
- In renal insufficiency with proteinuria, ramipril reduces renal decline better than amlodipine [53]
- ACE-I may halt or slow decline of muscle strength in women with HTN age >70 [62]
- Combination ACE-I with Ca2+ blockers or diuretics, other agents, are available
- ARB [66]
- As effective for HTN as ACE-I and better tolerated (much reduced cough)
- Confers clinical benefits beyond reduction in BP [63,64]
- 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]
- 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]
- Efficacy of ARB is increased with thiazide diuretic (such as HCTZ) added
- BP reduction slightly less than amlodipine but similar protection on CV outcomes [78]
- ARBs reduce risk of new development of DM compared with CCBs [78], diuretics and ß-blockers [22]
- ARB no better than standard therapy in treatment of patients with HTN and diastolic dysfunction [87]
- ß-Adrenergic Blockers [49]
- Generally not considered first line with overall increased risk of stroke [28] or DM2 [22]
- Should be used early in all patients with myocardial ischemia, MI, some arrhythmias
- Contraindicated in COPD, bradycardia, sick sinus syndrome
- Use any ß-blocker with care in the elderly who often have conduction system disease
- Less effective in blacks, but addition of diuretic often provides good results [79]
- Prevents reflex tachycardia when added to vasodilating Ca blocker or direct vasodilator
- Typical ß-blockers should be used with caution in diabetics unless post-MI
- ß-adrenergic blockers may increase risk of developing DM; this should be balanced against positive cardiac effects [41]
- ß-blockers with intrinsic sympathomimetic activity (ISA) may be used in patients who have conduction system disease, baseline bradycardia, or drug-related bradycardia
- ß-Blocker doses must be increased cautiously in patients with CHF
- Carvidilol uniquely improves glucose control and lipid metabolism in diabetics
- Labetolol is a mixed ß-blocker and alpha1-adrenergic blocker which is very potent
- In HTN patients with panic disorder or migraine, ß-blockers may be preferred
- Cardioselective agents do not adversely affect patients with asthma or other hyperactive airways disease [71]
- ß-blockers provide poor reduction in LV mass in LVH [35] but reduce AFib incidence [86]
- Calcium Channel Blockers (CCB) [11,12,31,47]
- Current agents are specific for L-type (long acting) calcium channels
- Long acting (once daily) CCB are effective and well tolerated
- Short acting CCB should not be used
- CCB are probably second line due to increased risk of CHF [11,12,46]
- For HTN with LVH, consider agents with anti-inotropic activity (verapamil, diltiazem)
- LVH: Verapamil superior to ß- blocker for reduction in LV mass
- Verapamil with ACE-I as effective and safe as ß-blocker with diuretic [13]
- Verapamil (controlled onset) neither superior nor inferior to diuretics or ß-blockers for initial treatment of HTN [76]
- Verapamil is safe but not superior to other agents for HTN treatment
- Diltiazem appears most effective in black patients (see above)
- Amlodipine (Norvasc®) generally safe, good BP reduction, easily combined
- Felodipine (Plendil®) 5mg/d well tolerated and clearly reduces HTN related mortality
- Diltiazem, ß-blockers and diuretics had similar effects on overall vascular mortility [44]
- Unclear if dihydropyridine CCB are detrimental in diabetics with HTN [43]
- Overall, CCB are safe and effective in DM with HTN, slight increase in CHF risk [11,12]
- Nisoldipine had ~10X increased risk of heart attacks in DM versus enalapril
- Nitrendipine safe and effective in elderly DM with systolic HTN [34]
- Long acting nifedipine as good as combination diuretic in reducing vascular mortality [45]
- Caduet® is amlopidine (Plendil®) in combination with atorvastatin (Lipitor®) [15]
- alpha1-Adrenergic Blockers
- Improve BP effectively as well as most of the common comorbidities
- 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]
- Prazosin is short acting agent and may cause syncopal events, particularly in elderly
- Longer acting agents (doxazosin, terazosin) are well tolerated when titrated
- Longer acting agents do not appear to induce tachyphylaxis and orthostasis
- Improve urinary symptoms in men with prostatic hyperplasia
- alpha2-Adrenergic Agonists
- Inhibit sympathetic outflow from Central Nervous System (CNS)
- Reduce blood pressure through vasodilation; little reduction in heart rate
- Clonidine is the most commonly used agent
- Monoxodine is also under development
- Direct Vasodilators
- Potent agents that cause marked reflex tachycardia
- Minoxidil and hydralazine are the major agents
- Should be used only in combination with a ß-blocker or verapamil or diltiazem
- Hydralazine - 40-200mg per day divided bid-qid
- Minoxidil - 2.5-40mg per day divided qd or bid (very potent agent)
- Caution with use of these agents which may exacerbate angina, other side effects
- Renin Inhibitor [25,26]
- Aliskiren (Tekturna®) is orally available, non-peptide selective renin inhibitor now approved
- Inhibition in first step in production of angiotensin
- Blood pressure reduction similar to ACE-I and ARB
- Do not affect degradation of BK
- May be particularly useful in combination with drugs that lead to reactive increase in renin including ACE-I, ARB, diuretics
- Combined aliskiren+valsartan reduces diastolic BP 12.2mm versus 9-10mm with either drug alone, versus 4mm with placebo [21]
- Do not cause angioedema
- Aliskiren dose is 150mg qd initially, then up to 300mg po qd
- Good synergy with diuretics and ARB
- Endothelin Receptor Antagonist
- Bosentan (Tracleer®) is an orally active, mixed ETa/ETb receptor antagonist [36]
- Administration of 100-2000mg/day reduces blood pressure (~12mm max)
- Bosentan increased plasma endothelin, mild reduction in angiotensin II
- As effective as enalapril in systemic HTN but ~20% develop liver function abnormalities
- Approved for pulmonary HTN
- Bosentan caused headache, flushing, leg edema, transaminase increases
- Darusentan reduces BP in patients wtih CHF but no effect on CHF symptoms [20]
- Aldosterone Blockade [77]
- Potassium sparing diuretics which block aldosterone receptors
- Moderate antihypertensive activity
- Effective in severe CHF
- Spironolactone (Aldactone®): 25mg po bid-tid initially (likely can be given qd; max 450mg/d)
- Eplerenone (Inspra®): 50mg po qd to start, up to 100mg po bid
- Main risk is hyperkalemia; monitoring is required
- Spironolactone has higher risk of gynecomastia than eplerenone
- Impotence and menstrual disturbances are uncommon with both agents
- Combination agents are available for most drug classes and have added efficacy
D. Effects of Anti-Hypertensive Therapy on Comorbid Conditions
- JNC-VII strongly recommende drug choices be made based on comorbid conditions [1]
- Adequate control of HTN is critical, particularly to slow progression of comorbid diseases
- Age, ethnicity, and to some extent renin profile, are considered in selecting agent [39]
- DM2
- ACE-I or ARB are ALWAYS the preferred agents
- ARBs for any ACE-I intolerant patients unless angioedema has occurred [4]
- DM2 incidence is lowest in HTN patients treated with ARB or ACE-I compared with other agents [22]
- alpha1-blockers improve metabolic profiles but may increase risk for CHF
- ß-blockers should be used with caution
- Hyperlipidemia [37,38]
- Thiazides and related agents increased cholesterol levels (effect may wane at 2 years)
- ß-blockers raised triglycerides slightly
- ß-blockers with intrinsic sympathomimetic activity lowered total cholesterol levels
- ACE-I lowered triglycerides and in diabetics, reduced total cholesterol levels
- Vasodilators excluding CCB lowered total cholesterol
- CCBs had no effect on cholesterol
- 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
- 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 ConditionsGroup: | Thiazides | ß-Blockers | ACE-I | ARB | CCB | a1-Blocker | a2-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
Mean Arterial Pressure (MAP)
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