michael j unruh, md renal associates of west michigan, pc€¦ · aldosterone antagonists...

Michael J Unruh, MD

Renal Associates of West Michigan, PC

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


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


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


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


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

Bibliography 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure:

the JNC 7 report. JAMA 2003; 289:2560.

2. Whaley-Connell AT, Sowers JR, Stevens LA, et al. CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004. Am J Kidney Dis 2008; 51:S13.

3. Buckalew VM Jr, Berg RL, Wang SR, et al. Prevalence of hypertension in 1,795 subjects with chronic renal disease: the modification of diet in renal disease study baseline cohort. Modification of Diet in Renal Disease Study Group. Am J Kidney Dis 1996; 28:811.

4. Diabetes Care 2013;36 (suppl 1) January 2013.

5. Zaman MA, Oparil S, and Calhoun DA. Drugs targeting the renin–angiotensin–aldosterone system. Nat Rev Drug Disc 2003; 1: 621.

6. Minutolo R, Agarwal R, Borrelli S, et al. Prognostic role of ambulatory blood pressure measurement in patients with nondialysis chronic kidney disease. Arch Intern Med 2011; 171:1090.

7. Buter H, Hemmelder MH, Navis G, et al. The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 1998; 13:1682.

8. Günal AI, Duman S, Ozkahya M, et al. Strict volume control normalizes hypertension in peritoneal dialysis patients. Am J Kidney Dis 2001; 37:588.

9. Alborzi P, Patel N, Agarwal R. Home blood pressures are of greater prognostic value than hemodialysis unit recordings. Clin J Am Soc Nephrol 2007; 2:1228.

10. Robinson BM, Tong L, Zhang J, et al. Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int 2012; 82:570.

11. Mailloux LU. The overlooked role of salt restriction in dialysis patients. Semin Dial 2000; 13:150.

12. Fishbane S, Natke E, Maesaka JK. Role of volume overload in dialysis-refractory hypertension. Am J Kidney Dis 1996; 28:257.

13. Santos SF, Peixoto AJ. Revisiting the dialysate sodium prescription as a tool for better blood pressure and interdialytic weight gain management in hemodialysis patients. Clin J Am Soc Nephrol 2008; 3:522.

14. Katzarski KS, Charra B, Luik AJ, et al. Fluid state and blood pressure control in patients treated with long and short haemodialysis. Nephrol Dial Transplant 1999; 14:369.

15. Tomson CR. Blood pressure and outcome in patients on dialysis. Lancet 2009; 373:981.

16. Tai DJ, Lim TW, James MT, et al. Cardiovascular effects of angiotensin converting enzyme inhibition or angiotensin receptor blockade in hemodialysis: a meta-analysis. Clin J Am Soc Nephrol 2010; 5:623.

17. Hörl MP, Hörl WH. Drug therapy for hypertension in hemodialysis patients. Semin Dial 2004; 17:288.

18. Flanigan MJ, Khairullah QT, Lim VS. Dialysate sodium delivery can alter chronic blood pressure management. Am J Kidney Dis 1997; 29:383.

19. Inrig JK, Patel UD, Toto RD, Szczech LA. Association of blood pressure increases during hemodialysis with 2-year mortality in incident hemodialysis patients: a secondary analysis of the Dialysis Morbidity and Mortality Wave 2 Study. Am J Kidney Dis 2009; 54:881.

michael j unruh, md renal associates of west michigan, pc€¦ · aldosterone antagonists...

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