hypertension and hyperlipidemia: latest diagnostic and ... › documents › 46 ›...

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Hypertension and Hyperlipidemia: Latest Diagnostic and Treatment

Options

Wendy L. Wright, MS, RN, ARNP, FNP, FAANPAdult/Family Nurse Practitioner

Owner – Wright & Associates Family Healthcare, PLLCPartner – Partners in Healthcare Education, LLC

Disclosures

• Grants: Novartis, Daiichi-Sankyo

• Speaker Bureau: Ortho-McNeill, Abbott, Novartis, GSK, Sanofi-Pasteur, Daiichi-Sankyo, Merck

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Objectives

• Upon completion of this lecture, the participant will be able to:

– Identify the various classifications of prehypertension, Stage I and Stage 2 hypertension; and the optimal ranges for various lipid parameters

– Discuss nonpharmacologic treatment options for the patient with hypertension and hyperlipidemia

– Discuss pharmacologic treatment options for the patient with hypertension and hyperlipidemia

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CVD Is the Most Common Health Problem in the United States

More than 60 million Americans

(>20%) have some form of

cardiovascular disease

Adapted from American Heart Association. Heart Disease and Stroke Statistics – 2003 Update. Dallas, Tex; 2002.

CVD disease mortality trends for males and femalesCVD disease mortality trends for males and females (United United

States: 1979States: 1979--2004). 2004).

SSource: NCHS and NHLBI.ource: NCHS and NHLBI.

400

450

500

550

79 80 85 90 95 00 04

Death

s in

Th

ou

san

ds

Years

Males Females

CVD disease mortality trends for males and females

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Evolution in Understanding Cardiovascular Disease: Total Risk Perspective

Cardiovascular Disease Is an Interplay of Risk Factors

Age Gender

SmokingDyslipidemia Hypertension

Diabetes

Mellitus

Kannel WB. Am J Hypertens. 2000;13:3S-10S; Poulter N. Am J Hypertens. 1999;12:92S-95S.

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Hypertension and Dyslipidemia Contribute to Atherogenesis

Endothelial

Dysfunction

CVD

Hypertension Dyslipidemia

Atherosclerosis

Smooth Muscle

Cell Contraction

Impaired Bioavailability

of Nitric Oxide

Impaired

Vasodilation

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Impact of Elevated SBP and Total Cholesterol on CHD Mortality in MRFIT

Age-Adjusted CHD

Death Rates

Per 10,000 Person-Years

Cholesterol

Quintile (mg/dL)

SBP Quintile (mm Hg)MRFIT = Multiple Risk Factor Intervention Trial.

Adapted from Neaton JD et al. Arch Intern Med. 1992;152:56-64.

33.7

21

17.1

12.7 12.2

22.6

12.3

8.3 9.6

5.9

17.7

10.98.5

6.35.5

16.7

7.9 7.96

4.3

13.7

5 5.63.4 3.1

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Impact of Hypertension

• 50 million individuals in the United States have hypertension1

• 277,000 deaths annually in US due to hypertension2

1American Association of Clinical Endocrinologists Medical Guidelines For Clinical Practice for the Diagnosis and Treatment of Hypertension. Endocrine Practice, Vol 12 No. 2 March/April 20062National Center for Health Statistics. Health, United States, 2005, with Chartbook on the Health of Americans. Hyattsville, Maryland: 2004. Available at: http://www.cdc.gov/nchs/hus.htm

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Hypertension Remains One of the Most Important Multipliers of CV Risk

BP >140/90 mm Hg is associated with:

• 277,000 deaths in 2003

BP, blood pressure; CHF, congestive heart failure; MI, myocardial infarction.

Rosamond W et al. Circulation. 2007;115:1-103.11Wright, 2012

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It is currently estimated that…

• 90% of normotensive 55 year olds will develop hypertension at some point in his/her lifetime

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Statistics

• Nearly 30% of all hypertensive individuals are unaware of their condition

– 42% are not being treated with antihypertensive medication

– 69% do not have their blood pressure (BP) controlled to the level recommended by JNC 7. 1,2

• The prevalence of hypertension will continue to increase as the population ages unless effective preventive actions are implemented.

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1 Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003;290:199-206.

2 The Seventh Report if the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 2003;289:2560-2572.

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Hypertension and Management:Old School

Hypertension = Systemic disease

Hemodynamics altered

Treat the blood pressure

Therapeutic options

BetaBlockers

ACE ARB Diuretics CCB Others

Adapted from Vascular Biology Working Group, University of FloridaCollege of Medicine, Carl Pepine, MD, DirectorWright, 2012

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Hypertension and Management: New School

Hypertension = Disease of the blood vessels

Vascular biology altered

Treat the vasculature

Therapeutic options

BetaBlockers

ACE ARB Diuretics CCB Others

Adapted from Vascular Biology Working Group, University of FloridaCollege of Medicine, Carl Pepine, MD, DirectorWright, 2012

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Physiology of the Renin Angiotensin System

Ang, angiotensin.

Reid IA. Adv Physiol Edu. 1998;20:S236-S245.

↓↓↓↓ BLOOD PRESSUREBLOOD VOLUME

Activation of Baroreceptor

Reflexes

↑↑↑↑ Renal Sympathetic Nerve Activity

Beta-adrenergicStimulation

↑↑↑↑ RENIN SECRECTION

↓↓↓↓ Renal Artery Pressure

Renal Baroreceptor

↑↑↑↑ BLOOD PRESSUREBLOOD VOLUME

SystemicVasoconstriction

↑↑↑↑ PlasmaAng II

↑↑↑↑ AldosteroneSecretion

↑↑↑↑ PlasmaAng I

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RAAS and Adipose Tissue

• All components of the RAAS system are expressed in adipose tissue, especially the visceral adipose tissue1,2,3

• Visceral adipose tissue of patients with insulin resistance and Type 2 diabetes is dysfunctional and is a source of chronic low-grade inflammation4

1 Sowers, James R. Insulin Resistance and Hypertension Physiol Heart Circ Physiol. 2004;286:H1597-H1602

2 Ashish, A, El-Atat, R, et al. Hypertension and Obesity Recent Prog Horm Res. 2004;59:169-205.3 Kershaw EE, Flier JS. Adipose Tissue as an Endocrine Organ Clin Endocrinol Metab. 2004;

98:2548-2556..Wright, 2012

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RAAS and Endothelial Dysfunction

• Growing body of evidence–Promotion of endothelial dysfunction

–Microalbuminuria1,2

• RAAS Inhibition (ACE, ARB and Direct Renin Inhibitor)–Decreased incidence of new onset Type 2 diabetes

– Improvement in CVD outcomes3

Higashi, Y, Sasaki S, Nakagawa K, et al. Endothelial Function and Oxidative StressIn Renovascular Hypertension N Engl J Med 2002;346:1954-1962.

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Today –The Hypertensive Patient Exhibits...

• More insulin resistance

• More hyperinsulinemia

• Dyslipidemia

• Microalbuminuria

• Obesity

...as compared to nonhypertensive patients!

Reaven GM. Banting lecture 1988. Role of insulin resistance in human. Disease Diabetes. 1988.37;1595-1607.

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Cardiovascular Disease

Hypertension

Diabetes

Blocking the RAAS has been shown to be beneficial in…

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JNC VII: Messages to Clinicians

JAMA. 2003:289:2560-2577.

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New Messages JNC VII

• The risk of CVD, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg.

JAMA. 2003:289:2560-2577.

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CV Disease Risk Doubles with

Each 20/10 mm Hg BP Increment*

*Individuals aged 40-70 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure

CVdisease

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

1. Lewington S, Cardiovascular Issues in Ageing Pilots. et al. Lancet. 2002; 60:1903-1913

2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, And Treatment of High Blood Pressure. http://jama.ama-assn.org/cgi/content/full/289.19.2560v1. Assessed 5-1-08

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Diagnosis

• 2 readings; separated apart

• Patient should not ingest caffeine or smoke for 30 minutes before readings

• Patient should sit for 5 minutes with arm at heart level before blood pressure is checked

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JNC 7: New Blood Pressure Classification

Blood Pressure ClassificationSBP* DBP*(mm Hg)

Normal

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Consider Secondary Causes of HTN

• Sleep apnea

• Drug-induced or drug related– Including OTC medications

• Chronic kidney disease– Polycystic kidneys

• Renal artery stenosis

• Primary aldosteronism

• Renovascular disease

• Chronic steroid therapy and Cushing’s disease

• Pheochromocytoma

• Coarctation of the Aorta

• Thyroid or parathyroid diseaseJAMA. 2003:289:2560-2577.

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What about White-Coat Hypertension?

• Patient involvement in the measurement of his/her blood pressure is recommended, particularly for those individuals whose blood pressure is normal out of the office but consistently elevated in the office

• The office blood pressure of elders is 5 mm Hg higher than their ambulatory blood pressure

• Older the individual, the greater the discrepancy between home and office blood pressures

• No longer considered a benign condition

JAMA. 2003:289:2560-2577.

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Initial Work-up

• History and review of systems

– Medications and risk factors

• Consider home blood pressure readings with validated blood pressure cuff

• Laboratory workup: CBC, BUN, Creatinine, Glucose, Lipids, GFR, urine - protein

• EKG and/or Echocardiogram, if indicated

• Urine for microalbuminuria Pickering, TG, Hall JE, et al. AHA Scientific Statement: Recommendations for Blood Pressure

Measurement in Humans and Experimental Animals. Part 1: Blood Pressure Measurement in Humans

Hypertension. 2005;45:142-161. Wright, 2012

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Treatment of Hypertension

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How Helpful is control of BP?

In stage 1 HTN, combined with additional CVD risk factors, achieving a sustained 12 mmHg reduction in SBP over 10 years will prevent 1 death for every 11 patients treated.

JAMA. 2003:289:2560-2577.

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Benefits of Lowering Blood Pressure

Average Percent Reduction

Stoke: 35% - 40%

MI: 20% - 25%

CHF: 50%

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation,And Treatment of High Blood Pressure. http://jama.ama-assn.org/cgi/content/full/289.19.2560v1. Assessed 5-1-08

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Treatment Goals

• < 140/90 mm Hg for those with no complications

• < 130/80 mm Hg for those with diabetes or CRF (per ADA)

• < 130/80 mm Hg – all individuals per NKF

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JNC 7: Algorithm for Treatment of Hypertension

Prehypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg)

Not at Goal BP (

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• The most effective therapy prescribed by the most careful clinician will control hypertension….only if the patient is motivated.

JAMA, May 21, 2003 Vol 289;No 19.

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Lifestyle Modifications to Manage Hypertension

Modification Recommendation Systolic Diastolic ChgsWeight Reduction BMI 18.5-24.9 5-20mm/10 kg wt loss

Adopt DASH eating Diet rich in fruits 8-14 mm Hg

vegetables and low

fat with reduced

saturated and total fat

Dietary Sodium 2.4g Na 2-8 mm Hg

Physical Inactivity Brisk exercise 30” day 4-9 mm Hg

most days of week

Moderation of

Alcohol intake 2 drinks day max 2-4 mm Hg

24 oz beer; 10 oz wine

2 oz 100 proof whiskeyJAMA. 2003:289:2560-2577.

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Lifestyle Modifications

• Dietary sodium reduction

–Most helpful in African Americans and patients with diabetes

–Recommend limiting sodium to < 2000 mg/day for these individuals

• Average individual ingests 4000 mg / day

–ACE inhibitors and diuretics work best with a relatively low sodium diet

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How Successful Is It?

• Combination of the DASH diet and a dietary sodium reduction to 1600 mg/day is as effective as 1 medication

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Alcohol Intake

• Limit alcohol intake to < 30 mL or 1 ounce of ethanol/day

– Translation: 2 ounces of whiskey

– 10 ounces of wine

– 24 ounces of beer

• Excessive amounts increases treatment resistance

• Also increases risk of a CVA** Women: ½ this amount

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Electrolytes

• Diets high in potassium, calcium and magnesium are associated with a lower blood pressure

• JNC VII recommends an adequate dietary intake of these but does not recommend supplementing from an outside source to lower blood pressure

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Additional Recommendations

• Omega-3 fatty acids may lower blood pressure

• Caffeine may increase it but tolerance often develops–Most studies do not support a relationship between hypertension and caffeine

• Smoking: discontinuation is important

• Exercise: 30 minutes daily recommended

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Pharmacologic Treatments

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• Thiazide diuretics should be used in drug treatment for patients with uncomplicated hypertension.

JAMA. 2003:289:2560-2577.

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Thiazide Diuretics

• Dosing:–Start @ 12.5 mg of HCTZ

– Increase to 25 mg at 6 weeks

• Benefits–55% reduction in CHF

–37% reduction in CVA

–27% reduction in cardiac events

• If not adequately controlled, add additional agents

Chlorthalidone

• Making a come back into thiazide arena

• Dosage: 25 mg once daily

• May increase dosage to 100 mg once daily

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Diuretic Precautions

• Electrolyte imbalances

• Syncope/presyncope when combined with ACE/ARB

• Hemoconcentration

• Decrease in urate excretion

• Worsening of insulin resistance at higher doses

• Fatigue

Product inserts accessed 04-20-2008Wright, 2012

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Angiotensin Converting Enzyme (ACE) Inhibitors

•Increased nitrous oxide at vessel for vasodilatation•Improved glucose disposal•Reduction in LV geometry changes•Reduction in inflammation•Stabilization of fibrous cap of lipid lesion•Decreased proteinuria •Improves endothelial function•Reduced mortality in patients with CHF•Decreases post-MI mortality

Sato Atsuhisa, Pleiotropic effects of angiotensin-converting enzyme inhibitors; differentiationAmong ace inhibitors may lead to further organ protection. Abstr 21st Sci Meet Int Soc Hypertens2006. 423(2006)

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ACE Inhibitor Trials

1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 2000 2001

CONSENSUS I

ValHeFT II

SOLVD treatment

SAVE

AIRE

TRACE

SMILE

CATS

CONSENSUS II

GISSI-3

ISIS-4

PEACE

HOPE

Latini, et al. Curr Perspect. 1995;92:3132-7

CCS-1

CHF

Anterior

AMI

AMI

CAD

LVD

Post-AMI

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ACE Inhibitors PrecautionsACE Inhibitors Precautions

• Hyperkalemia

• Increase in creatinine

• May improve insulin sensitivity

• Decrease in serum Na+ may result in syncope and dizziness when used with diuretics

Product inserts accessed 04-20-2009

• Angioedema

• Cough

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Effects on Hypoglycemia

• Several studies have shown the ability of ACE inhibition to improve glycemic control – even decrease the risk of hypoglycemia in patients using sulfonylureas.

Thamer M, Ray NF, Taylor T. Association between antihypertensive drug use and

hypoglycemia: A case-control study of diabetic users of insulin or sylfonylureas. Clin Therapeutics 1999; 21:1387

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But…

ACE InhibitorsAre Highly Effective..

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** ** ** **** ** ** **

* = p

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If you block the receptor

site, you don’t have to worry

about the angiotension levels…

AT1

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Angiotensin ReceptorBlockers

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Angiotension Receptor Blockers (ARB’s)

• Utilized since April 1995

• Blocks uptake at receptor site

• Angiotension II produced in locations other than in the lungs

• BP decreased by reducing vascular tone and enhancing NA+ and water clearance

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Metabolic Effects of ARB’sMetabolic Effects of ARB’s

• Angiotensin II Receptor Blockers

• Metabolically neutral

• No impact on lipids

• No impact on insulin

• No impact on K+

• Lowers uric acid levels

• Minimal side effect profile

Product Inserts accessed 04-20-2009Wright, 2012

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ARB Trials

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

ValHeFTELITE I

ELITE II

IDNT

RENAAL

IRMA II

OPTIMAAL

LIFE

VALIANT

VALUE

CHARM

MARVAL

ON TARGET

CHF

CV

MI

Renal/CV

Renal

IPreserve

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ACE vs ARBONTARGET Trial

Goal: 1. Assess the effects of ACE VS ARB in terms of efficacy

2. Assess if the combination ACE & ARB was superior

Results: Telmisartan was found to be “noninferior” to ramipril in patients with vascular disease or high risk diabetes

Combination of these two agents was associated with more adverse events without an increase in benefit.

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Yusuf, S, Teo KK, Pogue, J et al for the ONTARGET investigators. Telmisartan, ramipril, or both in patients At high risk for vascular events N Engl J Med 2008;358:1547-1559.

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Beta Blockers

•Reduction in blood pressure•Decreased contractility

•Decreased heart rate•Decreased myocardial oxygen

demand

•Reduction in LVH•Reduced arrhythmias


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Beta Adrenergic Receptors

• 3 receptors are found in human cardiac myocytes that are coupled to a positive inotropic response and cell growth.–Beta1–Beta2–Alpha1

Hunt, et al. ACC/AHA 2005 Chronic Heart Failure Guideline Update. JACC.2005; 46:1116-43.

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Beta Blocker Trials

SHEP Systolic Hypertension in the Elderly Program

Step Approach Chlorthalidone/Atenolol

Reduced incidence of major CV events

and CVA; chlorthalidone

decreased CHF

STOP HTN 2

Swedish Trial in Old Persons with

Hypertension

Beta Blocker Vs CCB VS ACE on CV Morbidity

ACE /BB similar efficacy in preventing

CV mortality.

CAPPP Captopril Prevention Project

Beta Blocker + Diuretic vs Captopril

Captopril not better than conventional

HTN Rx in prevention of CV morbidity and mortality; Diabetic

patients on captoprildid better than BB +Diuretics in

decreasing morbidity63

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Calcium Channel Blockers

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Calcium Channel Blockers

• Effectively treat systolic hypertension

• May be superior to other antihypertensives for stroke prevention

• Effective in patients with:

– Comorbid conditions (Raynauds, migraine)1

• Particularly effective in

– Elderly and African American’s2

1. Materson BJ, Reda DJ, eta l. Single drug therapy for hypertension in men. A comparison of sixAntihypertensive agents with placebo. N Engl J Med. 1993;328:914-921.

2. Tuomilehto J, Rastenyte D, et al. Effects of calcium channel blockade in older patients with Diabetes and hypertension. N Engl J med. 1999;340:677-684.

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The Calcium Blockers

Dihydropyridines

– Studies of DPH’s effects on

proteinuria have produced conflicting results

– NKF recommends that in

patients who have diabetes

and kidney disease, DPH’s should only be used in

combination with and ACE

or ARB

Nondihydropyridines

– Regression of proteinuria

– Combination of Verapamil +

ACE, reduction in proteinuria can be greater than

achievable with verapamil

alone.

– NKF now recommends adding a NDH to treat hypertension

with an ACE inhibitor or an

ARB to slow the progression of kidney disease.

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Thornley-Brown D, et al for the African American Study of Kidney Disease and Hypertension Study Group. Differing effects of antihypertensive drugs on the incidence

Of Diabetes mellitus among patients with hypertensive kidney disease. Arch Intern Med.2006;166(7):797-805.

National Kidney Foundation. K/DOQI clinical practice guidelines on hypertensionand antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;

43(suppl 1):S1-S290.Wright, 2012

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Alpha Blockers

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Alpha BlockersAlpha Blockers• Block postsynaptic Alpha1 Receptors

• Results in vasodilatation

• Relatively inexpensive

• Fair tolerability; May cause postural effects

• Additive agent for older men to decrease BPH symptomatology

• Add-on agent only

• Should never be used as monotherapy due to increased risk of stroke and CHF


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Centrally Acting Blockers

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Centrally Acting AgentsCentrally Acting Agents• Stimulates central alpha2 receptors which results in:

– Inhibiting efferent sympathetic activity

• Additive agents

• Should be used 3rd or 4th line

– Examples: Clonidine (catapress, catapress TTS); methyldopa

• Caution: sedation, orthostatic hypotension


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DirectVasodilators

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Direct VasodilatorsDirect Vasodilators

• Direct smooth muscle vasodilatation, primarily arteriolar

• Two agents

–Apresoline (Hydralazine)

–Minoxidil

**Precautions include: tachycardia, significant peripheral edema and hair growth

**Agents to reduce heart rate may be neededThe Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation,And Treatment of High Blood Pressure. http://jama.ama-assn.org/cgi/content/full/289.19.2560v1. Assessed 5-1-08

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Aldosterone Antagonists

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• Spironolactone (Aldactone)

• HCTZ / spironolactone (Aldactazide)

• Eplerenone (Inspra)


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Aldosterone as a Therapeutic Target

• Aldosterone promotes:–Retention of sodium

–Loss of magnesium and potassium

–Sympathetic activation

–Parasympathetic inhibition

–Baroreceptor dysfunction

– Impaired arterial compliance

Mac Fadyen RJ, et al Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 1997;35:30-34.

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• May be recommended in the following individuals:–Post MI

–NYHA Class III or IV

–Ejection fraction of < 35%

–Serum creatinine of < 2.5 mg/dl

–K+ < 5.0 mmol/LMardi Gomberg-Maitland, Baran DA, Fuster, V. Treatment of Congestive Heart FailureGuidelines for the Primary Care Physician and Heart Failure Specialist. Arch InternMed 2001;161:324-352et al. ACC/AHA 2005 Chronic Heart Failure Guideline Update. JACC.2005; 46:1116-43.


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Precautions• Must monitor electrolytes

• Must obtain baseline renal function

• Should discontinue the K+ supplement

• Should limit to use in severe heart failure and post MI patients

Clavell, Alfredo L. Common Mistakes made in the Treatment of Congestive Heart Failure. Success with

Failure: New Strategies for Evaluation and Treatment of CHF.

Whistler BC, Canada 8-2000.

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New Classes/Agents

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Direct Renin Inhibitor

Renin is the enzyme at thebeginning of the RAAS, oneof the key regulating centersfor blood pressure. Blockingthis enzyme can decrease the downstream impact of the RAAS system.

Suppression of the RAAShas been shown to treathypertension and reducetarget organ damage.

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Direct Renin Inhibition Inhibits the Entire Renin System1-4

Class

ACEI

ARB

Direct Renin Inhibitor (DRI)

PRA Ang I Ang II

Increased peptide levels have not been shown to overcome the blood pressure–lowering effect of these agents.ACEI, angiotensin-converting enzyme inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker;PRA, plasma renin activity.

1. Johnston CI. Blood Press Suppl. 2000;1:9(suppl 1):9-13.

2.Widdop RE et al. Hypertension. 2002;40:516-520.

3.Fabiani ME et al. Angiotensin II Receptor Antagonists. 2001:263-278.

4. Lin C et al. Am Heart J. 1996;131:1024-1034.80Wright, 2012

Aliskiren

� Dosage:

–150 mg or 300 mg once daily

� Indications:

–Adults with hypertension

Product Insert, 200781Wright, 2012

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New Warning re: Aliskiren

• Do not combine with ACE or ARB

• Avoid use of valturna

–Aliskiren and valdasartan

• Warning followed after early termination of the ALTITUDE trial

–Offered no benefit and was associated with an increased risk of CVA’s

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European Medicines Agency

• The EMA has announced plans to review all aliskiren products and, until the results of this review are available, it has recommended that:

– Aliskiren-containing medicines should not be prescribed to diabetic patients who are also taking an ACE inhibitor or an ARB

– Prescribers should review patients taking aliskiren at a routine (non-urgent) appointment and, if patients are diabetic and are also taking ACE inhibitors or ARBs, aliskiren should be stopped and alternative treatments considered

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http://www.pjonline.com/clinical-pharmacist/2012_jan/avoid_aliskiren_with_ACE_inhibitors_and_ARBs accessed 01-12-2012

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• Certain high risk conditions are compelling indicationsfor the initial use of other antihypertensive drug classes.

– Angiotensin-converting enzyme inhibitors

– Angiotensin-receptor blockers

– Beta blockers

– Calcium channel blockers

JAMA. 2003:289:2560-2577.

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JNC 7: Compelling Indications for Individual Antihypertensive Drug Classes

Compelling

Indication*

Recommended Drugs

DIURETIC BB ACEI ARB CCBAldo

ANT

Heart failure • • • • •

Post-MI • • •

High coronary disease

risk• • • •

Diabetes • • • • •

Chronic kidney disease • •

Recurrent stroke

prevention• •

*Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed parallel with the BP.

ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; Aldo ANT = aldosterone antagonist; BB = beta-blocker; CCB = calcium channel blocker.

Adapted from NHBPEPCC. 2003. NIH Publication No. 03-5233.

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Combination Therapy

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When you put your hand in the cabinet…

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JNC 7 (2003)Combination Therapy

• Most hypertensive patients will require

two or more antihypertensive

medications to achieve goal BP

(

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Target Organ Damage

• Heart

– LVH, Angina, CHF, MI

• Brain

– Stroke or TIA

– Dementia

• Chronic Kidney Disease

• Peripheral Vascular Disease

• Retinopathy

JAMA. 2003:289:2560-2577.

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Pick the agent wisely

•Benefits are not the same in antihypertensive therapy at the same commensurate blood pressure control.

American Heart Association Scientific Sessions 2003; November 9-12, 2003,Orlando, Florida, USA.

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Hyperlipidemia

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Many Patients Are Not Reaching Their LDL-C Goal

Adapted from Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

0

10

20

30

40

50

60

70

80

90

100

Low Risk High Risk CHD

Diet/exercise (%)

Drug therapy* (%)

Percent of Patients

Achieving Goal

*Included statins (fluvastatin, lovastatin, pravastatin, simvastatin), gemfibrozil, bile acid sequestrants, niacin, psyllium fiber, or combination drug therapy

282 861 361 1924 108 1352n =

59

70

21

40

8

18

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LDL Is the Primary Target

• LDL is the primary target of reduction

– All should be < 100

• Anyone with an LDL > 160 – candidate for pharmacotherapy

• Only exception is the patient with triglycerides > 400 – 500

– Then…target triglycerides first

– Reduce LDL as second goal

96Wright, 2012

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ATP III Recommendations

• Persons with diabetes without CHD raised to level of CHD risk equivalent

• Same for patients with CVD, PVD, aortic aneurysm and chronic renal failure

– This means-LDL must be reduced to under 70

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

97Wright, 2012

Landmark Statin Trials: LDL-C Levels vs Events

Pe

rce

nta

ge

wit

h C

HD

ev

en

t

Primary prevention

Pravastatin

Lovastatin

Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21

Atorvastatin

10

5.4 (210)2.3 (90) 2.8 (110) 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190)

WOSCOPS-S WOSCOPS-P

0

5AFCAPS-S AFCAPS-P

9

8

7

6

4

3

2

1

ASCOT-P

ASCOT-S

LDL-C, mmol/L (mg/dL)

S = statin treated; P = placebo treated

98Wright, 2012

The Problem with Estimating LDL-C

*Scharnagl H et al. Clin Chem Lab Med 2001 May;39(5):426-31

Estimated or Friedewald LDL-C = TC – HDL-C – TG/5

- Assumes TG to Cholesterol ratio in each VLDL particle is a constant

- Breaks down when TG > 200 or < 100

- Breaks down if you do not fast

- Breaks down when LDL is low

When LDL is 93 mg/dL then Friedewald is 15% falsely low*

When LDL is 61 mg/dL then Friedewald is 19% falsely low*

99Wright, 2012

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• Low HDL-C:

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Advanced Lipoprotein Panel Highly Abnormal

Basic Lipid Panel –Abnormal

TC= 123LDL = 77

HDL = 24

Trigs= 162

Insulin ResistantAbundance of Lg VLDLAbundance of LDL SmallAbundance of HDL Small

Highly Atherogenic

103Wright, 2012

Insulin Resistance

Syndrome

104Wright, 2012

105Wright, 2012

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106Wright, 2012

Structure of HDL

Rye KA et al. Atherosclerosis 1999;145:227-238.

Hydrophobic CoreHydrophobic Coreof Triglyceride of Triglyceride and Cholesterol and Cholesterol EstersEsters

apoAapoA--IIII

Surface Surface Monolayer of Monolayer of Phospholipids Phospholipids and Free and Free CholesterolCholesterol

apoAapoA--II

107Wright, 2012

Industrial StrengthMost protective

Dust BusterLeast protective

The HDL Molecules(s)

108Wright, 2012

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109Wright, 2012

hsCRP

110Wright, 2012

hsCRP

• CRP is hepatically derived family of proteins that are nonspecific, acute-phase reactant proteins

– CRP normally circulates at very low levels

– Acute inflammatory processes, infections, or tissue injuries induce a marked increase in hepatic synthesis of CRP, which can induce a 100-fold serum increase

Gotto, A.M: Contemporary Diagnosis and Management of Lipid Disorders, 3rd ed. Newtown, Pennsylvania,Handbooks in Health Care Co., Inc. 2004.

111Wright, 2012

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hsCRP

• Atherosclerosis is now linked in part to chronic, low-level inflammation of the vascular endothelium

• Hence, the association with elevated levels of hsCRP

Gotto, A.M: Contemporary Diagnosis and Management of Lipid Disorders, 3rd ed. Newtown, Pennsylvania,Handbooks in Health Care Co., Inc. 2004.

112Wright, 2012

Studies Regarding C-reactive Protein

• 3 year study

• 28,000 postmenopausal healthy women

• High-sensitivity CRP: strongest single predictor of future cardiac events

• Highest levels of ultrasensitive CRP: 5 fold increased risk of developing CHD and a 7 fold increase of having an MI or stroke

Ridker, P.M et. al. C-reactive protein and other markers of inflammation in the

prediction of cardiovascular disease in women. New Engl J Med. 2000;342:836-43.113Wright, 2012

Additional Studies

• Ridker et al. 1998 found an increased risk of cardiovascular events in patients with a baseline hsCRP of 6.6 when compared with a level of 1.2 mg/L–75% greater risk of cardiovascular events

114Wright, 2012

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Study Regarding Obesity and hsCRP

• Human fat cells produce a protein that is linked to both inflammation and an increased risk of heart disease and stroke

• Explains why people who are overweight generally have higher levels of the C-reactive protein (CRP)

Willerson, J.T. et. al. Journal of the American College of Cardiology, September 2005

115Wright, 2012

Who Should Be Tested for hsCRP?

• Individuals who, according to the Framingham Risk Assessment Tool, are at an intermediate risk for the development of cardiovascular disease (10 – 20% risk)

www.aha.org accessed 01/28/07116Wright, 2012

Who Should Be Tested for hsCRP?

• Not for widespread screening of the general adult population; continue to focus on major risk factors, such as high blood pressure, high cholesterol, smoking and diabetes

• Useful as an independent marker of risk and as a “discretionary tool” in the evaluation of those with moderate cardiovascular disease risk to determine treatment course

www.aha.org accessed 01/28/07117Wright, 2012

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Other Expert’s Disagree….

• Many experts believe that this test should be conducted on all patients

–36 studies to date have been conducted on the link between hsCRP and CAD

–All 36 studies have shown a positive relationship

• PHS, WHS, MONICA, ARIC, NHS, HPFS, CHS, EPIC-Norfolk, PIMA are just a few of the studies to show a positive correlation between elevated hsCRP and increased risk for CAD

Ridker, P. Apollo Lecture Series. Brigham and Women’s Hospital; Boston, Mass 2005.

118Wright, 2012

Laboratory Measurements

• hsCRP

– < 1.0 mg/L - low risk of developing cardiovascular disease1

– 1.0 and 3.0 mg/L - average risk1

– > 3.0 mg/L - high risk1

– In the past, it was said that if hsCRP is > 10 mg/L; it was unlikely to be related to cardiovascular inflammation

NO LONGER BELIEVED TO BE TRUE!!1http://www.americanheart.org/presenter.jhtml?identifier=4648 accessed 01/28/07

119Wright, 2012

High vs. Low hsCRP

• This study showed that approximately 10% of the population has an hsCRP level that is undetectable.

–These individuals have an incredibly low event rate and low plaque rupture rate

• Individuals with hsCRP > 10 – 20 had the highest event rate (about 7 fold higher than the individual with a low hsCRP) Ridker, PM. Circulation, 2004; 109:1955-1959

120Wright, 2012

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How Do We Treat hsCRP?

• Lifestyle modification

–Dietary and exercise modifications leading to weight reduction

–Smoking cessation

• Weight loss

–12 weeks of a low-fat diet, hsCRP decreased by 26% in healthy obese women

–Does this reduce events?? Stay tuned…..

Heilbronn LK, Noakes, M, Clifton PM: Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women. Arterioscler Thromb Vasc Biol2001;21:968-970. 121Wright, 2012

How Do We Treat hs-CRP?

• Statins–Can reduce hsCRP by 29% - 50% (fluvastain ER)

– In another study, simvastatin, pravastatin and fluvastatin all reduced CRP by 45%, 66% and 76%

–Best outcomes may be LDL < 70 mg/dL and hsCRP < 2 mg/L

Gotto, A.M: Contemporary Diagnosis and Management of Lipid Disorders, 3rd ed. Newtown, Pennsylvania, Handbooks in Health Care Co., Inc. 2004.

http://www.medscape.com/viewarticle/502691_6 accessed 01/28/07

122Wright, 2012

What is the Target?

• PROVE-IT TIMI 22 Trial

–Patients were randomized to 40 mg/day of pravastatin vs. 80 mg/day of atorvastatin

–Reducing hsCRP to < 2 mg/L improved event-free survival in all patients with ACS regardless of LDL levels

– Lowering hsCRP < 2 was protective even when the LDL was > 70 mg/dL

Internal Medicine World Report, March 2005

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What is the Target?

• REVERSAL Trial–502 patients with documented CHD

–Randomized to 40 mg/day of pravastatin vs. 80 mg/day of atorvastatin• Patients randomized to atorvastatin had less progression of atherosclerosis

–Reducing hsCRP levels provided a benefit in atherosclerosis progression that was independent of the LDL lowering

Nissen, S. NEJM. 2005;352:20 – 28, 29 – 38124Wright, 2012

Treating hsCRP

• Niacin has been shown to reduce hsCRP

• Aspirin has also been shown to reduce hsCRP

• TZD’s and ACE inhibitors can reduce hsCRP

• Omega-3 fatty acids can reduce hsCRP

Hong H, Xu ZM, Pang BS, Cui L, Wei Y, Guo WJ, Mao YL, Yang XC. Effects of simvastain combined with omega-3 fatty acids on high sensitive C-reactive protein,lipidemia, and fibrinolysis in

patients with mixed dyslipidemia. Chin Med Sci J. 2004 Jun;19(2):145-9.

125Wright, 2012

Treatment Options

126Wright, 2012

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HMG CoA Reductase Inhibitors

• Action

– Inhibit the HMG CoA reductase enzyme

– Enzyme is essential for the synthesis of cholesterol

– Also increases the uptake of LDL by the liver

– Additional properties:

• Smooth muscle cell proliferation, platelet aggregation and deposition, fibrinogen, endothelial vasodilation and blood viscosity are also affected by the statins

• May indicate that these medications should be used with diabetes, hypertriglyceridemia, and for stroke prevention

127Wright, 2012

* Nonfatal MI/CHD death

‡ Primary Prevention† Secondary Prevention

** Normal cholesterol levels

The Lancet 1994;344:1383-1389 JAMA 1998:279:1615-1622.

N Engl J Med 1995;333:1301-1307. N Engl J Med 1998;339:1329-1357

N Engl J Med 1996;335:1001-1009

Recent Landmark Coronary Prevention Recent Landmark Coronary Prevention Recent Landmark Coronary Prevention Recent Landmark Coronary Prevention Recent Landmark Coronary Prevention Recent Landmark Coronary Prevention Recent Landmark Coronary Prevention Recent Landmark Coronary Prevention StudiesStudiesStudiesStudiesStudiesStudiesStudiesStudiesStudy Drug N Duration

(Years)Main Findings

4S† simvastatin 4,444 5 ↓↓↓↓30% total mortality

↓↓↓↓34% coronary events*

WOS‡ pravastatin 6,595 5 ↓↓↓↓31% coronary events

↓↓↓↓22% total mortality

CARE† **

pravastatin 4,159 5 ↓↓↓↓24% coronary events

↓↓↓↓31% stroke

AFCAPS/TexCAPS‡ **

lovastatin 6,605 5 ↓↓↓↓37% coronary events/unstable angina Low HDL population

LIPID† pravastatin 9,014 6 ↓↓↓↓22% total mortality

↓↓↓↓24% death from CHD

128Wright, 2012

Events* in the Major Prevention TrialsEvents* in the Major Prevention TrialsEvents* in the Major Prevention TrialsEvents* in the Major Prevention TrialsEvents* in the Major Prevention TrialsEvents* in the Major Prevention TrialsEvents* in the Major Prevention TrialsEvents* in the Major Prevention Trials*Nonfatal MI/CHD death

Trial N # of # of RR % Events

Events Events Reduction Not Avoided

Placebo Statin %

4S 4444 622 431 34 69

WOS 6595 248 174 31 70

CARE 4159 274 212 24 77

AFCAPS/ 6605 215 163 25 76

TexCAPS

LIPID 9014 715 557 24 78

129Wright, 2012

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Important Information

• Statins may increase risk of diabetes

– Studies now confirm this in both men and women

• Statins may be administered to children age 10 and up with markedly elevated LDL’s unresponsive to traditional therapy

• Rule of 6’s

• Newest statin: pitavastatin (Livalo)

• No longer need to monitor liver enzymes on scheduled basis; clinician judgement

Wright, 2012 130

Why Are We Reducing Events By Only 24%

• 80% of individuals are on monotherapy with statins

– Majority of individuals are in need of combination therapy

• Must consider each component of the lipid panel independently

– A great LDL does not negate the risks associated with a low HDL

– A great HDL does not negate the risks associated with a high LDL

• Target LDL 1st – unless trigs > 400 – 500

• Then target - HDL

131Wright, 2012

-----

*Risk of coronary heart disease over 4 years of follow-up for men ages 50 to 70.

CORONARY HEART DISEASE RISK

HDL vs. LDL as a PredictorHDL vs. LDL as a PredictorHDL vs. LDL as a PredictorHDL vs. LDL as a Predictor

0.0

1.0

2.0

3.0

100 160 220 8565

4525

LDL (mg/dl)LDL (mg/dl)

HDL (mg/dl)HDL (mg/dl)

Risk of CHD Data from Framingham Study

After 4 Yrs*

3.0

2.0

1.0

132Wright, 2012

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Framingham Data…

• This landmark study very clearly demonstrated that for every 4 mg/dL HDL is decreased, there is a 10% increase in CAD

• This is independent of any other risk factors

133Wright, 2012

Framingham Offspring Study: Multiplier for HDL-Cholesterol Level*

HDL HDL

cholesterolcholesterol

3030

3535

4040

4545

5050

5555

6060

6565

7070

MenMen

1.821.82

1.491.49

1.221.22

1.001.00

0.820.82

0.670.67

0.550.55

0.450.45

——

WomenWomen

——

——

1.941.94

1.551.55

1.251.25

1.001.00

0.800.80

0.640.64

0.520.52

Castelli WP. Castelli WP. Am Heart J.Am Heart J. 1983;106:11911983;106:1191--1200.1200.

**Relative increase or decrease of CHD risk according to HDL cholesterol value. Relative increase or decrease of CHD risk according to HDL cholesterol value. Multiply the patient’s general risk by the number opposite the HDL cholesterol value.Multiply the patient’s general risk by the number opposite the HDL cholesterol value.

134Wright, 2012

Nicotinic Acid

• Examples

–Niacin (Immediate release)

–Niaspan (Extended release)

135Wright, 2012

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Niacin – OTC Preparations

• Recent study of “NO flush Niacin” products revealed:

–None of the 8 products marketed as no flush niacin had any niacin in them

Prescriber’s Letter, 2004136Wright, 2012

Mechanism of Action of Niacin

Niacin

↓Adipose tissue ↓FA synthesis/

FA mobilization esterification

↓TG Synthesis

↓Large TG-rich

VLDL

↓ Small dense LDL

↓ Assembly of Apo B containing

Lipoproteins / ↑ Apo B

degradation

↓VLDL, LDL

Niacin

↓ HDL-catabolism

receptor

↓ HDL Apo A-1

Uptake/removal

↑ Apo A-1/reverse

Cholesterol

Transport137Wright, 2012

VA-HIT Results: Major Study Showing HDL Improvement Does Matter!

-35

-30

-25

-20

-15

-10

-5

0

5

10

LDL HDL TG Non fatal

MI

CHD-

Death

Stroke

% C

han

ge

% C

han

ge

N Engl J Med. 1999:341:410-418† Investigator designated

0%0%

6%6%**

-31%31%**

--23%23%** --22%22%****

--29%29%**

*p≤0.05

**p=0.07

†

138Wright, 2012

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Not Everyone Deserves Niacin

• Recent information:

– Individuals with heart disease and LDL < 70 mg/dL show no benefit from increasing HDL with niacin (AIM HIGH TRIAL)

–High dose Niacin was added to simvastatin

–Studied was concluded at 18 months when no benefit was seen; followed for 36 months

–Despite raising HDL, no improved outcomes

Wright, 2012 139

What About Combination Therapy?

• Increasingly becoming the norm

• Particularly in individuals with insulin resistance syndrome

• HATS Trial addressed this issue

140Wright, 2012

HATS Trial:HDL–Atherosclerosis Treatment Study

• 160 CAD patients– HDL < 40 mg/dL in women

– HDL < 35 mg/dL in men

• Randomized– Simvastatin (13 mg/d) and niacin (mean 2.4 g/d)

– Antioxidants (Vitamin E, vitamin C, Beta-carotene, selenium

• Outcomes– CV events (death, MI, stroke, revascularization)

– Arteriographic change in coronary stenosis

• Follow-up, 3 years141Wright, 2012

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*P

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Bile Acid Sequestrants

• “Resins”

• Indications: Hyperlipidemia; Particularly LDL

• Examples:

–Cholestyramine (Questran)

–Colestipol (Colestid)

–Colesevelam HCL (Welchol)145Wright, 2012

Welchol

• Welchol (Colesevelam HCL)

• Dosage: 625 mg

– 3 tablets bid or 6 tablets qd; Maximum 7 tablets/day

• With a statin: 4 – 6 tablets daily

– Take with food

• Indications

– Adjunct to diet and exercise to reduce LDL cholesterol

– May be used alone or in combination with a statin

146Wright, 2012

Welchol

• Results

–LDL reduction: 2% - 20% (lowest –highest doses)

–Total cholesterol reduction (8%)

–HDL improvement (8 – 11%)

–May increase triglycerides

147Wright, 2012

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• Side effects

–GI side effects are the most common

–Elders: may be at risk for a fecal impaction

–Decreased vitamin/medication absorption

–May also increase bleeding tendencies

148Wright, 2012


• Precautions

–Decreased absorption of thyroxine, digoxin, anticoagulants, thiazide diuretics, propranolol, furosemide, statin drugs

–Dose these medications 1 hour before or 4 hours after the bile acid binding resins

149Wright, 2012

Fibric Acid Derivatives

• “Fibrates”

• Indications

–Hypertriglyceridemia with a family history of atherosclerosis

• Examples

–Lopid (gemfibrozil)

–Tricor (fenofibrate)

150Wright, 2012

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• Mechanism of Action

–Increase the clearance of VLDL from the plasma and therefore increase the secretion of cholesterol into bile

• Dosing

–Lopid (gemfibrozil): 600mg bid

–Tricor (fenofibrate): •48 mg and 145 mg once daily

151Wright, 2012


• Results

–Triglyceride reduction: 20-50%

–HDL increase: 10-15%

–LDL +/-

– Limited data regarding long-term benefits of fibrate therapy

• Side effects

–Generally well tolerated

152Wright, 2012


• Side effects

–Gastrointestinal complaints including nausea, dyspepsia, abdominal and epigastric pain, vomiting

–Rash

–Accentuates anticoagulants

–Elevated LFTs

153Wright, 2012

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Significant FDA Warnings

• Combination of fibrate including fenofibric acid (Trilipix) in combination with statin

• Increased risks of rhabdomyolysis

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Ezetamibe (Zetia): A Cholesterol Absorption Inhibitor

• Dosage: 10 mg once daily

• Efficacy: 18% reduction in LDL when used as monotherapy

–When added to a statin – 25% reduction in LDL

155Wright, 2012

Other Therapies

156Wright, 2012

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Formerly - Omacor Now - Lovaza

• Omega-3 Fatty Acids

• 1 gram capsules

• Dosages: 4 capsules daily

• Indications: reduce triglyceride levels in excess of 500 mg/dL

• Precautions: bleeding, anticoagulants

• Side effects: Burping

157Wright, 2012

Fish Oils

• AHA recommending 1 gram per day of fish oils for those with heart disease

• First prescription drug containing omega – 3 fatty acids (EPA and DHA)

• Lowers triglycerides as much as 45%

–More concentrated (meaning they contain 3x more EPA and DHA than OTC products)

158Wright, 2012

One Regimen

• Flax Seed daily– Shown to reduce total cholesterol and LDL

– No research to support lower morbidity and mortality

• Red Yeast Rice daily– Previously equivalent to approximately 10 mg of lovastatin (Mevacor)

– No longer the case

– No statin-like active ingredient

159Wright, 2012

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Benecol

• Benecol, Right Start, Take Control

–All spreadable “margarine” like products that have been shown to reduce LDL by approximately 15%

–Can certainly be added to statin, niacin, fibrate or bile acid sequestrant

•Dosage: 2 – 3 tbsp per day

160Wright, 2012

Advances in the Prevention of CHD

• LDL-C

• HDL-C

• Lipid subclasses

• C-reactive protein

• Combination

therapy

161Wright, 2012

Thank You For Your Time and Attention!

162Wright, 2012

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Wendy L. Wright, ARNPAdult/Family Nurse [email protected]

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