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Michael J Unruh, MD
Renal Associates of West Michigan, PC
None
The Definition of Hypertension 1940s: >210/100
1950s: >180/110 1960s: >160/105 1977 (JNC I): >160/95 1984 (JNC III): >140/90 1993 (JNC V): >130/85 2003 (JNC VII): >120/80 2013 (JNC 2013): ?
Definition of hypertension (JNC 7) (no compelling indications)
Normal: < 120 and < 80
Pre-HTN: 120-139 or 80-89
Stage 1: 140-159 or 90-99
Stage 2: >160 or > 100
Definition of hypertension (JNC 7) (with compelling indications)
Normal: < 120 and < 80
Pre-HTN: 120-129 and < 80
Stage 1: 130-159 or 80-89
Stage 2: >160 or > 100
Compelling indications:
1. Cardiovascular disease
2. Diabetes mellitus
3. Chronic kidney disease
Definition of hypertension JNC 2013?
In June, ESH/ESC recommended a SBP goal of 140-150 mmHg in patients under the age of 80
Goal DBP was less than 85 mmHg
While HHS has not yet approved JNC 2013, it is expected to follow suit:
Goal blood pressures <140/90 in hypertension and chronic kidney disease
Goal blood pressure <140/80 in diabetes mellitus
Goal systolic blood pressure <150 if age 80 or older
Ideal systolic blood pressure 140-144
Prevalence of hypertension Hypertension is the most common primary diagnosis in this
country 50 million Americans affected (28%)
1 in 5 adults
NHANES data 1999-2002 63% know they have hypertension 45% are being treated 34% are at goal by JNC VII criteria
Healthy People 2010 goal: from 28% to 16% Actually increased to 39% by 2006
Hypertension facts Starting at 115/75:
For every rise in SBP of 3-4 mmHg, the risk of heart attack increases by 20% and stroke by 12%
Starting at 115/75:
For every rise in SBP of 20 mmHg or DBP of 10 mmHg, the risk of heart attack or stroke doubles
If left untreated, 60% of prehypertension will progress to stage 1 hypertension in 4 years
Hypertension facts Patients with risk factors and a SBP of 140-160:
lowering SBP by 12 mmHg will prevent one death for every 11 patient treated over 10 years
Patients with compelling indications and a SBP of 140-160:
lowering SBP by 12 mmHg will prevent one death for every 9 patients treated over 10 years
Hypertension has momentum Age causes hypertension
Increased aortic and peripheral vascular stiffness
Hypertension causes hypertension Endothelial damage and smooth muscle hypertrophy
increase blood pressure
Currently in the US: Most patients need 2 or more drugs to reach goal Most patients with diabetes need 3-4 drugs to reach goal
Basic treatment algorithm <120 and <80: no intervention
120-130 and <80: encourage lifestyle modification
130-140 and 80-90
0-2 risk factors: lifestyle
3 or more risk factors: lifestyle + meds
Any compelling indication: lifestyle + meds
>140 or >90: lifestyle + meds
Assessing risk Risk factors: Compelling indications:
Hyperlipidemia Cardiovascular disease
Smoking Diabetes mellitus
Family history Chronic kidney disease
Insulin resistance
Sedentary lifestyle
Lifestyle Modifications Weight loss and systolic blood pressure:
1 kg loss can lead to 1 mmHg SBP reduction (up to 6 mmHg)
Sodium intake and systolic blood pressure: Normal: 150 mmol (3.5g)
Reduced: 100 mmol (2.3g) – 2 mmHg drop
Extreme reduction: 50 mmol (1.2g) – 7 mmHg drop
DASH diet: 50 mmol (1.2g) – 9 mmHg drop
Exercise
Moderation of alcohol intake
Pathophysiology of Hypertension Basic hemodynamics
Cardiac output (heart rate and stroke volume) Peripheral vascular resistance
Neuro-hormonal axis Renin-Angiotensin-Aldosterone System (RAAS) Catecholamines
Small bed vascular resistance Endothelial dysfunction Vasoactive substances
RAAS
Zaman MA, Oparil S, and Calhoun DA. Drugs targeting the renin–angiotensin–aldosterone system. Nat Rev Drug Disc 2003; 1: 621.
Initial treatment Hypertension is extraordinarily heterogeneous
There is no single “holy grail” of hypertension therapy
Targeting patient specific pathology is only in early stages Works best in known secondary hypertension
For the most part, first line therapy is still “one size fits all”
First line drugs by class A – ACE inhibitors / ARBs
B – β-blockers (?)
C – Calcium channel blockers
D – Thiazide-type Diuretics
ACE Inhibitors / ARBs Should be used in diabetics regardless of proteinuria
Not recommended as dual therapy in most patients
Recommended as tolerated in patients with heart failure or post-myocardial infarction
ACEI / ARB may reduce fasting glucose
Lab monitoring: initial therapy, increased dose, addition of new med, yearly monitoring
ACE Inhibitors / ARBs Mechanism of Action:
Angiotensin II Receptor Blockers
Causes vasodilation, decreased aldosterone production/ secretion, and decreased vasopressin secretion
Angiotensin Coverting Enzyme Inhibitors
Block conversion of Angiotensin I to Angiotensin II
A note on β-blockers β-blockers are going out of favor as a first line med in the
general population Higher stroke risk
Higher all-cause mortality
ESH/ESC specifically recommends against use, except in: Post-myocardial infarction
Heart failure
Atrial fibrillation
Only atenolol is evidence-based β-blockers are not as effective at lowering central BP
This may result in increased cardiovascular outcomes
β-blockers Types:
β-1 specific: atenolol, metoprolol, nebivolol
Nonselective: propranolol
Nonselective + α: carvedilol, labetalol
Side effects:
Impaired exercise tolerance
Can increase fasting glucose levels (4-6mg/dl) and cause weight gain
Can cause pulmonary exacerbation, lethargy, nightmares, and decreased sexual drive
Calcium channel blockers Two classes:
Dihydropyridines: ending in -ipine Non-dihydropyridines: the others
Dual calcium channel blockade can provide an additive BP lowering effect
Long acting agents are not contraindicated in heart failure Amlodipine can help with pulmonary hypertension Verapamil may help with left ventricular remodeling in
diastolic heart failure
Thiazide-type diuretics MUST have a salt restricted diet for efficacy Dose thiazides adequately:
HCTZ 50-100 mg/day reduces BP No evidence of effect on CV outcomes!
Chlorthalidone 12.5-25 mg/day reduces BP, CV outcomes Indapamide 1.25-2.5 mg/day reduces BP, CV outcomes
Chlorthalidone and Indapamide are thus the drugs of choice in this class
Thiazides augment the BP lowering effect of other drugs when used in combination (more than a purely additive effect)
Thiazide-type diuretics Side effects:
Might increase fasting glucose by 4-6 mg/dl
Can cause hypokalemia
Can cause hyponatremia
Increase serum uric acid
Preventing thiazide induced hypokalmeia may prevent increase in fasting glucose
Lab monitoring: initial therapy, increased dose, addition of new med, yearly monitoring
Drugs for special populations Blacks: calcium channel blockers and thiazides possible
more effective than ACE inhibitors / ARB
Women of child bearing age: no ACEI / ARB without pregnancy counseling
Elderly: thiazides most effective but monitor for electrolyte complications
Diabetics: ACEI / ARB and thizaide combination is first line
Drugs for special populations Lung disease: dual calcium channel blockers Post MI: β-blockers are first line Heart failure: β-blockers are first line Anxiety disorder: dual catecholamine blockade (α- and β-
blocker) and an SSRI Subclinical anxiety (pseudo-pheochromocytoma): paroxysms
of hypertension without overt anxiety
Brief, Confusing Slide Thiazide β-blocker ACEI ARB CCB Aldosterone
antagonist Clinical Trial Basis
Heart Failure x
x
x
x
x
x
ACC/AHA HF guideline; MERIT-HF; COPERNICUS, CIBIS, SOLVD; AIRE, TRACE, Val-HeFT; RALES
Post-MI x
x
x
x
ACC/AHA post-MI guideline; BHAT; SAVE, CAPRICORN, EPHESUS/VALIANT
High CAD risk x
x
x
x
x
ALLHAT; HOPE, ANBP2; LIFE; CONVINCE, ONTARGET
Diabetes mellitus
x
x
x
x
NKF-ADA guideline; UKPDS; ALLHAT
Chronic kidney disease
x
x
NKF guideline; CAPPP; RENAAL; IDNT, REIN, AASK
Stroke x
x
x
PROGRESS, LIFE
Adapted from Chobanian AV et al. JAMA.2003;289:2560-2572
Common medications Lisinopril: 10-40mg 1 /day
Enalapril: 5-20mg 2 /day
Valsartan: 90-180mg 2 /day*
Losartan: 25-100mg 1 /day
Atenolol: 25-100mg 2 /day*
Metoprolol: 25-100mg 2 /day
Carvedilol: 6.25-25mg 2 /day
Labetalol: 100-900mg 2-3 /day*
Common medications Amlodipine: 5-10mg 1 /day
Nifedipine ER: 30-90mg 1/ day
Diltiazem ER: 120-360mg 1 /day
Verapamil SR: 120-240mg 2 /day*
HCTZ: 25-50mg 2 /day*
Chlorthalidone: 25-50mg 1 /day
Spironolactone: 25-100mg 2 /day
Resistant hypertension Resistant hypertension
Not meeting goal on maximum doses of 3 meds including a diuretic
Uncontrolled hypertension
Not meeting goal but non-adherence or inadequate therapy persists
Resistant Hypertension Characteristics:
Older
Higher baseline blood pressure
Chronic kidney disease
Diabetes mellitus
Obesity
Excessive sodium intake
Left ventricular hypertrophy
African American
Female
Uncontrolled hypertension Non-adherence is one of the main factors contributing to
perceived resistance
Adherence needs to be actively assessed
On average in the primary care setting, 40% of patients will stop initial therapy within the first year
Switch to generics, low cost combinations, or 3 month supplies
Referral: non-adherence rates dropped to 16% when patients saw a hypertension specialist
Uncontrolled hypertension Dose inadequacy is the other main factor contributing to
perceived resistance Maximize dosage (especially of thiazides) Review dosage intervals
Review lifestyle modifications (EVERY TIME) Re-enforce salt restriction for diuretic efficacy
Look for interfering substances NSAIDs, alcohol, diet pills, decongestants
Encourage home monitoring
Secondary hypertension Chronic kidney disease Drug-induced (NSAIDs, antidepressants, stimulants) Obstructive sleep apnea (OSA) Renal artery stenosis Primary aldosteronism Hypercortisolism (Cushing disease) Thyroid disease Hyperparathyroidism Pheochromocytoma Oral contraceptive use
Secondary hypertension Suspect secondary HTN with new onset, severe, or rapidly
accelerating HTN
OSA is the most common unrecognized cause
Drug-induced is also very common
RAS can be associated with intolerance of ACEI/ARB by renal function
25-30% Creatinine increase expected
Hyperaldosteronism is more prevalent than previously estimated Hypokalemia is probably a late manifestation
Drug classes Second line (in my personal favorite order):
Aldosterone antagonists Alpha blockers Direct vasodilators Central alpha agonists
Others (population specific use only): Long acting nitrates Loop diuretics Direct renin inhibitor
Aldosterone antagonists Spironolactone, eplerenone
Primary aldosteronism more prevalent that previously thought
Effective dosage may be as high as 100-200 mg twice a day
Aldosterone ‘escape’ can be a mechanism of resistant HTN Not a function of random renin/aldosterone levels
Effective at dosage of 25-50mg per day
Obese patients generate more aldosterone
Aldosterone antagonists Indicated in low dose for heart failure
Eplerenone less likely to cause gynecomastia
Very weak diuretics (even with thiazides) except in edematous states
Lab monitoring: initial therapy, increased dose, addition of new med, yearly monitoring
Alpha-1 blockers Doxazosin, Terazosin Once daily dosing to be dosed at night Likely not as effective if patient is already on carvedilol or
labetalol Can help with benign prostatic hypertrophy and may
increase insulin sensitivity May worsen heart failure Side effects: first pass orthostasis, headache, fatigue
Direct vasodilators Hydralazine, minoxidil Hydralazine is a potent arterial vasodilator
Needs to be dosed 3 times a day
Minoxidil is a potent venous vasodilator Not recommended to use in combination Common side effects:
Edema (use in combination with a diuretic) Tachycardia (use in combination with a β-blocker)
Central alpha agonists Clonidine Patch is available but less effective than the equivalent oral
dose The pill needs to be dosed 3 times a day for 24 hour
coverage Every 8 hour dosing is the most effective
Common side effects: fatigue, dry mouth, CNS depression, constipation, urinary retention
Rebound hypertension will occur if stopped suddenly Significant dependence on renal clearance α-methyldopa still occasionally used
Long acting nitrates Used specifically in the post-MI and angina population Not a recommended routine second line agent May have a role in elderly-associated isolated systolic
hypertension and diastolic heart failure Caveat: specifically designed to not have 24-hour coverage
Loop diuretics Furosemide, Bumetanide, Torsemide
Can be antihypertensive, but only in edematous states complicated by kidney disease
Kidney disease prolongs clearance
Not recommended for eGFR > 30 ml/min/1.73m2
Lab monitoring: initial therapy, increased dose, addition of new med, yearly monitoring
Direct renin inhibitor Aliskerin (Tekturna) available since March 2007
Equivalent to ACEI / ARB / CCB in combination with thiazides but no data for monotherapy
AVOID trial: reduced proteinuria, no clinical benefit
ALTITUDE trial: increased non-significant rate of hypotension, stroke
As a result of the above trials, not recommended to combine with ACEI or ARB therapy
Lab monitoring: initial therapy, increased dose, addition of new med, yearly monitoring
Common medications Spironolactone: 25-50mg 1-2 /day
Eplerenone: 25-50mg 1-2 /day
Doxazosin: 1-8mg 1 /day at bedtime
Terazosin: 1-5 mg 1 /day at bedtime
Clonidine: 0.1-0.3mg 3 /day
Hydralazine: 25-100mg 3 /day
Minoxidil: 5-20mg 2 /day
Furosemide: 40-120 mg 3-4 /day
Bumetanide: 1-3 mg 2 /day
Torsemide: 20-80 mg 1 /day
Aliskiren: 150-300 mg 1 /day
Chronic kidney disease Hypertension present ~85% of the time
Based on the MDRD study:
65% of patients with an GFR of 85 ml/min/1.73m2
95% of patients with an GFR of 15 ml/min/1.73m2
Chronic kidney disease Due to:
Sodium retention
Increased renin-angiotensin activity
Enhanced sympathetic nervous system activity
Decreased nitric oxide synthesis due to uremia
Hyperparathyroidism induced vasoconstriction
Hypercalcemia induced vasoconstriction
Erythropoietin therapy
Chronic kidney disease BP goals (KDIGO 2011), likely JNC 2013
If no proteinuria, <140/90
If proteinuria present, less than 130/80
BP goals in diabetes mellitus (ADA 2013)
Less than 140/80, though a goal of less than 130/80 may be appropriate in some individuals
Chronic kidney disease SODIUM RESTRICTION!
More effective than valsartan with normal sodium diet
Loop diuretics
Particularly when GFR < 30 ml/min/1.73m2
Longer acting (bumetanide, torsemide)
Volume expansion may be present despite lack of edema
ACEI/ARB, CCB, aldosterone antagonists remain effective
End stage kidney disease Dialysis BP is misleading
Predialytic pressures typically overestimates
Postdialytic pressures typically underestimates
Ambulatory and home pressures preferred
Optimal pressure
Unclear
Mortality clearly high if SBP >160 predialysis
However, mortality also increased if <140/90 predialysis
Lower pressures associated with more access thrombosis
End stage kidney disease “Hypertension in dialysis patients is volume until proven
otherwise”
Estimated dry weight
BP normalizes or symptoms of hypovolemia appear
Post dialysis BP normalized and no edema or orthostasis
May be complicated by:
Antihypertensives
High dialytic sodium bath
Short dialysis sessions
End stage kidney disease Effective drugs include:
ACE inhibitors
ARBs
Calcium channel blockers
Beta-blockers in selected patients
Clonidine
Direct vasodilators
End stage kidney disease Unique issues
High sodium bath
Leads to sodium uptake during dialysis
Solution: use a lower sodium or variable sodium bath
Hypertension during dialysis
Poorly understood
Associated with worse outcomes
May respond to carvedilol
Trials ALLHAT (2002): ACEI vs CCB vs TD
ASCOT (2005): CCB+ACEI vs BB+TD
VALUE (1998): ARB vs CCB
INVEST (2003): BB+ACEI vs CCB+ACEI
TROPHY (2006): ARB vs placebo
HOPE (2000): ACEI+others vs others
LIFE (2002): ARB+TD vs BB+TD
Others: RENAAL, SHEP, ACCORD, DREAM, FACET,
ABCD, ADVANCE, HOT, AVOID, ALTITUDE, ACCOMPLISH
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