1

Management of Hypertension

Ghada A Bawazeer. MSc, Pharm.D., BCPSIbrahim Sales, Pharm.D.

Assistant Professors-Clinical Pharmacy DeptCollege of Pharmacy

Sept. 2013

Most diagnoses occurring between the third and fifth decades of life.

Hypertension accounts for significant morbidity and mortality

One billion individual suffer from hypertension worldwide ( 26%). WHO year 2000 estimation

Seven millions deaths/year are attributed to hypertension

Billions of dollars are spent annually in direct and indirect cost of hypertension

Background

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Elkhalifa et al (2011): prevalence of HTN 26%

Alzahrani (2011): prehypertension 37%, hypertension 18%

Alshehri (2008): 57.8% in diabetic patients

Hypertension in Saudi Arabia

Data from National Health & Nutrition Examination Survey (NHNES)

National Health and Nutrition Examination Survey (NHANES), United States, 2003–2010◦Controlled 46.5%◦Uncontrolled 53.5%

Unaware 39.4% Aware and not treated 15.8% Aware and treated 44.8 %

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BP Control Rate

What is the recommendation for BP screening?

JNC VII Age:> 18 yrs Every 2 yrs if normal Recheck in 1 yr if Pre–HTN Stage 1 - Confirm in 2

months Stage 2 - Confirm in 1

month If > 180 / 110, treat now

NICE Age: >40 yrs Recheck in 5 yrs if

normal Recheck freq if Pre–HTN If > 180 / 110, treat now

No National policy in KSA

Blood Pressure Classification:JNC VII

BP Classification

SBP mmHg DBP mmHg

Normal < 120 and < 80

Pre - HTN 120 - 139 or 80 - 89

Stage 1 HTN 140 - 159 or 90 - 99

Stage 2 HTN > 160 or > 100

Isolated Systolic HTN

> 140 < 90

Blood Pressure Classification:2007 European Societies of HTN and

CardiologyBP Classification SBP mmHg DBP mmHg

Optimal BP < 120 < 80

Normal 120 - 129 and /or 80 - 84

High Normal 130 - 139 and /or 85 - 89

Grade 1 140 - 159 and / or 90 - 99

Grade 2 160 - 179 and / or 100 - 109

Grade 3 > 180 and / or > 110

Isolated Systolic HTN >140 < 90

ISH according to NICE: SBP >160 and DBP <90 mm Hg

Strong correlation between BP and CV morbidity and mortality.

Risk increases Patients with prehypertension SBP vs DBP

Cardiovascular Risk and Blood Pressure

Essential HTN ◦ > 90% unknown causes

Genetics monogenic and polygenic forms of BP dysregulation

Genes affect sodium balance, urinary kallikrein excretion, nitric

oxide release, excretion of aldosterone, and angiotensinogen

Etiology

Secondary◦ <10% have identifiable causes

removing the offending agent (when feasible) or treating/correcting the underlying comorbid condition should be the first step in management.

Etiology

A: Accuracy, Apnea, Aldosteronism ( ) B: Bruits, Bad Kidneys: RAS / Renal Parenchyma/ Pheochromocytoma C: Cushings, Coarctation of Aorta, Catechol ( ) D: Drugs, Diet E: Erythropoietin ( ), Endocrinopathies/

Multiple factors that control BP are potential contributing components in the development of essential hypertension:◦ Genetics◦ Cardiac output◦ Sodium regulation◦ RAAS system◦ Sympathetic drive◦ Peripheral resistance◦ Vascular endothelium and smooth muscle ◦ Electrolyte

Hypertension Pathophysiology

How much blood flow

How much resistance to

blood flow

BP

Total peripheral resistance (TRP)

Cardiac Output(CO)

Increase pre-load Increased fluid volume

excess sodium intake renal sodium retention

Venous constriction: Excess stimulation of

RAAS Sympathetic

Functional vascular constriction and/or Structural vascular hypertrophy

Excess stimulation of the RAAS ↑ Sympathetic Genetic alterations of cell

membranes Endothelial-derived factors Hyperinsulinemia (metabolic

syndrome)

Renin-Angiotensin-Aldosterone System (RAAS)◦Very complex endogenous system ◦Controlled mainly by the kidney Influences vascular tone and sympathetic nervous

system activity Sympathetic nervous system

Neuro-Humoral Mechanisms

BP: 140-179 / 90-109BP: 140-179 / 90-109

ABPM (If available)

ABPM (If available)

Office BPM

Office BPM

Home BPM (If available)Home BPM

(If available)

Yes

Hypertension Visit 2Target Organ Damage

or Diabetesor BP ≥ 180/110?

Hypertension Visit 2Target Organ Damage

or Diabetesor BP ≥ 180/110?

Hypertension Visit 1BP Measurement,

History and Physical examination

Hypertension Visit 1BP Measurement,

History and Physical examination

HypertensiveUrgency /

Emergency

HypertensiveUrgency /

Emergency

Diagnosisof HTN

Diagnosisof HTN

No

Diagnostic algorithm for hypertension

Criteria for the diagnosis of hypertension and recommendations for follow-up

BP: 140-179 / 90-109BP: 140-179 / 90-109

ABPM (If available)ABPM (If available)

Diagnosisof HTN

Awake BP>135 SBP or>85 DBP or

24-hour>130 SBP or

>80 DBP

Awake BP>135 SBP or>85 DBP or

24-hour>130 SBP or

>80 DBP

Awake BP<135/85

and24-hour<130/80

Awake BP<135/85

and24-hour<130/80

Continue to follow-up

Office BPOffice BP

Diagnosisof HTN

Hypertension visit 3 >160 SBP or >100 DBP

>140 SBP or>90 DBP

< 140 / 90

Diagnosisof HTN

Continue to follow-up

<160 / 100

Hypertension visit 4-5

ABPM or HBPM

or

Home BPMHome BPM

>135/85>135/85 < 135/85 < 135/85

Diagnosisof HTN

Continue to follow-up

Patients with high normal blood pressure (office SBP 130-139 and/or DBP 85-89) should be followed annually.

Repeat Home BPM

Repeat Home BPM

If< 135/85

If< 135/85

Blood pressure measurement◦Based on average of > 2 accurate

measurements taken during two or more clinical encounters

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Diagnosis

Patient Evaluation Routine Laboratory Tests :

1. Urinalysis2. Blood chemistry (potassium, sodium and creatinine)3. Fasting glucose4. Fasting total cholesterol and high density lipoprotein

cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglycerides

5. Standard 12-leads ECG6. Microalbuminurea (if diabetic patient)

Patient Evaluation Optional Laboratory Tests

◦ Investigation in specific patient subgroups For those with diabetes or chronic kidney disease:

assess urinary albumin excretion, since therapeutic recommendations differ if proteinuria is present.

For those suspected of having an endocrine cause for the high blood pressure, or renovascular hypertension, see following slides.

Other secondary forms of hypertension require specific testing.

Assess global cardiovascular risk in all hypertensive patients

91%

Rantala A, et al. J Intern Med 1999;245;163-74. Wannamethee S, et al. J Hum Hypertens 1998;12;735-41

Risk factors = Global CV risk

91% of hypertensive patients have at least 1 additional risk factor

III. Assessment of the overall cardiovascular risk

Cardiovascular Risk Factors • Presence of Risk Factors

– Increasing age– Male gender– Smoking– Family history of premature cardiovascular disease (age< 55 in men and < 65 in women)– Dyslipidemia– Sedentary lifestyle– Unhealthy eating– Abdominal obesity– Dysglycemia (diabetes, impaired glucose tolerance, impaired fasting glucose)

• Presence of Target Organ Damage– Microalbuminuria or proteinuria– Left ventricular hypertrophy– Chronic kidney disease (glomerular filtration rate < 60 ml/min/1.73 m2)

• Presence of atherosclerotic vascular disease– Previous stroke or TIA– Coronary Heart Disease– Peripheral arterial disease

CV Risk Factors that may alter thresholds and targets in the treatment of HTN

Methods of Risk Assessment

• Clinical impression• Risk factor counting• Risk calculation or equation tools

• Framingham hard coronary heart disease (CHD)http://www.framinghamheartstudy.org/risk/hrdcoronary.html

• SCORE Canada – Systematic Cerebrovascular and Coronary Risk Evaluation www.score-canada.ca

• Cardiovascular Age™ www.myhealthcheckup.com • Others: see notes

Will be discussed in more details during PPL 3 and Dyslipidemia

lecture

Optimal goal of BP is still debatable J-curve phenomena: not conclusive

hypothesis Current evidences have many limitations to

conclusively support 140/90 or 130/80 in HTN without diabetes, or <130/80 in patients with diabetes, CKD

There is a trend towards better outcomes with the lower range

What is the optimal BP target in hypertensive patients?

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JNC7 2003

AHA 2007

NICE 2011

CHEP 2013

ESC2009

No co-morbidConditions

<140/90 mm Hg

BP within 130-

139/80-85 mm Hg

Patients with

Diabetes <130/80 mm Hg

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Blood pressure treatment goals among the different guidelines

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Blood pressure treatment goals among the different guidelines

JNC7 2003

AHA 2007

NICE 2011

CHEP 2013

ESC2007

Patients with Known coronary artery disease

(MI, stable angina, unstable angina)

Noncoronary atherosclerotic

vascular disease (ischemic stroke, TIA, PAD, abdominal aortic

aneurysm) FRS > 10%

No specific recommendatio

n

<130/80 mm Hg

No specifi

c recommenda

tion

<140/90 mm Hg

Suggesting it is wise to lower to < 130/80

Patients with left ventricular dysfunction

(heart failure)

<120/80 mm Hg

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Blood pressure treatment goals among the different guidelines

JNC7 2003

AHA 2007

NICE 2011

CHEP 2013

ESC2007

Patients with CKD <130/80

<130/80 <140/90 <140/90 Not

clear

Elderly population (>80 yr)

<140/90

<140/90 <150/90 <150/90

<140/90

Management of Hypertension

Patient-oriented outcome: ◦Reducing CV risk◦reduce HTN-associated morbidity and mortality. target-organ damage (e.g., CV events,

cerebrovascular events, heart failure, kidney disease).

Surrogate ◦ to achieve a desired target BP

a tool that clinicians use to evaluate response to therapy

Not a guarantee of prevention of hypertension-associated TOD

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Goals of Therapy

Lifestyle modification

AND

Pharmacological therapy

Approach to Treatment

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Lifestyle Recommendations for Prevention and Treatment of Hypertension

To reduce the possibility of becoming hypertensive,Reduce sodium intake to less than 1500 mg/day • Healthy diet: high in fresh fruits, vegetables, low fat dairy products,

dietary and soluble fibre, whole grains and protein from plant sources, low in saturated fat, cholesterol and salt in accordance with Canada's Guide to Healthy Eating.

I. Regular physical activity: accumulation of 30-60 minutes of moderate intensity dynamic exercise 4-7 days per week in addition to daily activities; For non-hypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise (such as free weight lifting, fixed-weight lifting, or handgrip exercise) does not adversely influence blood pressure.

• Low risk alcohol consumption: (≤2 standard drinks/day and less than 14/week for men and less than 9/week for women)

• Attaining and maintaining ideal body weight (BMI 18.5-24.9 kg/m2)• Waist Circumference: Men <102 cm Women <88 cm• Tobacco free environment

Impact of Lifestyle Therapies on Blood Pressure in Hypertensive Adults

Intervention Intervention SBP/DBP

Reduce sodium intake-1800 mg/day sodium

Hypertensive-5.1 / -2.7

Weight loss per kg lost -1.1 / -0.9

Alcohol intake -3.6 drinks/day -3.9 / -2.4

Aerobic exercise 120-150 min/week -4.9 / -3.7

Dietary patternsDASH diet

Hypertensive -11.4 / -5.5

Padwal R et al. CMAJ 2005;173;(7);749-751

Lifestyle Therapies in Adults with Hypertension: Summary

Intervention Target

Reduce foods with added sodium < 2300 mg /day

Weight loss BMI <25 kg/m2

Alcohol restriction < 2 drinks/day

Physical activity 30-60 minutes 4-7 days/week

Dietary patterns DASH diet

Smoking cessation Smoke free environment

Waist circumference Men <102 cm Women <88 cm

Drug Therapy for Hypertension

Use first line classes◦ACE, ARB, CCB, Diuretics, BB◦All classes demonstrated CV risk reduction benefits Major determinant in reduction of Cardiovascular

Risk is BLOOD PRESSURE REDUCTION recommend treatment with drugs taken only once a

day. recommend generic where appropriate and minimize

cost.

General Principles

Population SBP DBP

High risk (TOD or CV risk factors) 140 90

Low risk (no TOD or CV risk factors) 160 100

Diabetes 130 80

Lifestyle modification is recommended for all regardless of BP

II. Indications for PharmacotherapyUsual blood pressure threshold values for initiation of pharmacological treatment for hypertension

TOD=target organ damage

Target Organ Damage (TOD) Cerebrovascular disease

◦ transient ischemic attacks◦ ischemic or hemorrhagic

stroke◦ vascular dementia

Hypertensive retinopathy Left ventricular

dysfunction Left ventricular

hypertrophy

Coronary artery disease◦ myocardial infarction◦ angina pectoris◦ congestive heart failure

Chronic kidney disease◦ hypertensive nephropathy

(GFR < 60 ml/min/1.73 m2)◦ albuminuria

Peripheral artery disease◦ intermittent claudication◦ ankle brachial index < 0.9

Stage 1 HTN◦ No TOD, low CV risk

Life style modification (LS)◦ TOD, moderate-high risk

LS + drug therapy Stage 2 HTN

◦ LS + drug therapy JNC 7 recommend 2 combination therapy as initial

therapy Isolated Systolic HTN

◦ When BP >140/90 mm Hg

When to initiate drug therapy?

Algorithm for treatment of HTN

degree of BP

elevation

presence of compelling Indications

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III. Treatment of Adults with Systolic/Diastolic Hypertension WITHOUT Other Compelling Indications

TARGET <140/90 mmHg

INITIAL TREATMENT AND MONOTHERAPY

*BBs are not indicated as first line therapy for age 60 and above

Beta-blocker*

Long-actingCCB

Thiazide ACEI ARB

Lifestyle modificationtherapy

ACEI, ARB and direct renin inhibitors are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential

A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target

III. Considerations Regarding the Choice of First-Line Therapy

• ACEI, renin inhibitors and ARBs are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential.

• BBs are not recommended as first line therapy for patients age 60 and over without another compelling indication.

• Diuretic-induced hypokalemia should be avoided through the use of potassium sparing agents if required.

• The use of dual therapy with an ACEI and an ARB should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy.

• ACEI are not recommended (as monotherapy) for black patients without another compelling indication.

Chlorthalidone is the diuretic that was use in most of the influential trials

It is 2X more potent in lowering BP on a mg-per-mg basis than HCTZ

HCTZ has not been as extensively studied in major long term hypertension clinical trials.

It is not definitively known if the clinical benefits of reducing CV morbidity and mortality that have been proven with chlorthalidone can be extrapolated to HCTZ.

In clinical practice, however, CV benefits in hypertension apply to all thiazide-type diuretics, and benefits are considered a class effect.

Does the CV benefits seen in ALLHAT for Chlortahlidone extend to hydrochlorothiazide?

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Add-on Therapy for Systolic/Diastolic Hypertension without Other Compelling

Indications

IF BLOOD PRESSURE IS NOT CONTROLLED CONSIDER

• Nonadherence• Secondary HTN• Interfering drugs or lifestyle• White coat effect

If blood pressure is still not controlled, or there are adverse effects, other classes of antihypertensive drugs may be combined (such as

alpha blockers or centrally acting agents).

2. Triple or Quadruple Therapy

1. Add-on Therapy

If partial response to monotherapy

III. Summary: Treatment of Isolated Systolic Hypertension without Other Compelling Indications

CONSIDER

• Nonadherence• Secondary HTN• Interfering drugs or

lifestyle• White coat effect

Thiazide diuretic

Long-actingDHP CCB

Dual therapy

Triple therapy

Lifestyle modificationtherapy

ARB

TARGET <140 mmHg, < 150 mmHg for age > 80 years

*If blood pressure is still not controlled, or there are adverse effects, other classes of antihypertensive drugs may be combined (such as ACE inhibitors, alpha blockers, centrally acting agents, or nondihydropyridine calcium channel blocker).

Option 1: Increase the dose of the first agent, remember:◦ Dose response curves for efficacy are relatively flat

◦ 80% of the BP lowering efficacy is achieved at half-standard dose

Option 2: Add another drug from the 1st line classes◦ Combinations of standard doses have additive blood

pressure lowering effects.

Partial response

Most patients will require 2 or more agents to achieve BP control

Consider combination from among the first line drugs Different possible combinations, consider patient factors

and cost. CHEP GL:

◦DHP-CCB + Diuretic ◦DHP-CCB + ACEI or ARB ◦DHP-CCB + BB

Combination therapy

Use combination from first line classes Many fixed-dose combination products are

commercially available, consider patient factors and cost◦some are generic

Most products contain a thiazide-type diuretic and have multiple dose strengths available.

Individual dose titration is more complicated with fixed-dose combination

Considerations when Selecting a Combination Therapy

ACEI + ARB, not recommended (Grade A) If a diuretic is not used as first or second line

therapy, triple dose therapy should include a diuretic, when not contraindicated

If a BB was used initially, a CCB is preferred over thiazide-type diuretic, to reduce the person’s risk of developing diabetes.

Caution should be exercised in combining anon-DHP CCB and a BB to reduce the risk of bradycardia or heart block

Considerations when Selecting a Combination Therapy

Use caution in initiating therapy with 2 drugs in whom adverse events are more likely (e.g. frail elderly, those with postural hypotension or who are dehydrated).

Considerations when Selecting a Combination Therapy

Choice of antihypertensive agentHTN with compelling indications:

Choice of Pharmacological Treatment for Hypertension

Individualized treatment• Compelling indications:

– Ischemic Heart Disease– Recent ST Segment Elevation-MI or non-ST Segment Elevation-MI– Left Ventricular Systolic Dysfunction– Cerebrovascular Disease– Left Ventricular Hypertrophy– Non Diabetic Chronic Kidney Disease– Renovascular Disease– Smoking

• Diabetes Mellitus– With Nephropathy– Without Nephropathy

• Global Vascular Protection for Hypertensive Patients– Statins if 3 or more additional cardiovascular risks– Aspirin once blood pressure is controlled

2013 Canadian Hypertension Education Program (CHEP)

Important messages from past recommendations

• Patients with diabetes are at high cardiovascular risk

• Most patients with diabetes have hypertension

• Treatment of hypertension in patients with diabetes reduces total mortality, myocardial infarction, stroke, retinopathy and progressive renal failure rates.

• Treating hypertension in patients with diabetes reduces death and disability and reduces health care system costs

• In diabetes, TARGET <130 systolic and <80 mmHg diastolic

• If a patient has both diabetes and CKD, TARGET <130 systolic and <80 mmHg diastolic

• The use of the combination of ACE inhibitor with an ARB should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy.

XII. Treatment of Hypertension in association with Diabetes Mellitus: Summary

More than 3 drugs may be needed to reach target values for diabetic patients

If Creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired

Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg

Diabetes

withNephropathy

> 2-drug combinations

ACE Inhibitoror ARB

withoutNephropathy

1. ACE Inhibitor or ARB

or2. DHP-CCB or

Thiazide diuretic

Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB

Combinations of an ACEI with an ARB are specifically not recommended in the absence of proteinuria

A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target. Combining an ACEi and a DHP-CCB is recommended.

ACCORD Study: Results and rationale for lack of impact on BP recommendations

• Overall BP study was neutral with no benefit of systolic target < 120 mmHg vs < 140 mmHg for primary outcome, yet:

• Power issue: Annual rate of primary outcome 1.87% in the intensive arm versus 2.09% in the standard arm vs 4%/year event rate projected during sample size calculations

• Significant interaction between BP and glycaemia control studies such that those in usual care glycaemia group (A1c 7%+) had a significant improvement in primary outcome with lower BP target

• Secondary outcome for stroke reduction showed a benefit for lower BP target (41% RRR)

• Therefore no clear evidence supporting a change in BP targets for people with diabetes at this point

ACCORD study NEJM 2010

Not first line therapy in uncomplicated HTN by almost all guidelines

Doesn’t reduce CV risk as does ACEI/ARB, CCB, diuretics in patients with only HTN.

Consider to use if compelling indication present (MI, CAD, HF)

those with an intolerance or contraindication to ACEI or ARBs, CCB

women of child-bearing potential people with evidence of increased sympathetic drive.

When would you consider BB?

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Alternative Antihypertensive agents

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Hypertension management in Selected

Populations

Isolated systolic hypertension is common in the elderly◦Treat similar to previous discussion

What about the very elderly? Studies showed HTN in the very elderly (>80 yrs)

should be treated◦HYVET trial: reduced mortality at BP <150/90

What is the goal of BP in the very elderly?◦Not clear

Elderly

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Use diuretics with caution: susceptible to volume depletion Elderly patients are more sensitive to :

◦ volume depletion and sympathetic inhibition than younger patients orthostatic hypotension >> dizziness >> increase risk of

falls Use caution with diuretics, ACEI, and ARBs provide significant

benefits and can safely be used in the elderly,◦ Start at low initial doses

Avoid centrally acting agents and alpha-blockers

Elderly

Orthostatic Hypotension◦SBP decrease of ↓ more than 20 mm Hg or DBP

↓more than 10 mm Hg when changing from supine to standing.

Risk factors: elderly, DM, severe volume depletion, baroreflex dysfunction, autonomic insufficiency, and use of venodilators

Start with low doses of the antihypertensive agent

Patients susceptible to orthostatic Hypotension

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HTN in pregnancy major cause of maternal and neonatal morbidity and mortality.

Preeclampsia:◦Elevated BP > 140/90 that appears after 20 weeks

gestation accompanied by new-onset proteinuria (> 300 mg/24 hours). life-threatening complications for mother and fetus.

◦Definitive treatment of preeclampsia is Delivery

HTN & Pregnancy

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Eclampsia:◦onset of convulsions in preeclampsia. ◦A medical emergency. ◦Treatment: Delivery restricting activity, bed rest, and close monitoring. Antihypertensives prior to induction of labor if DBP is

> 105 mm Hg with a target DBP of 95 to 105 mm Hg. IV hydralazine (common), IV labetalol Immediate-release oral nifedipine should not be used

HTN & Pregnancy

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Gestational hypertension:◦ New onset hypertension after mid-pregnancy, no

proteinuria chronic hypertension

◦ elevated BP that is noted before the pregnancy began◦ Treatment:

consensus about most appropriate therapy in pregnancy is lacking

Methyldopa is still considered the drug of choice Other agents are listed in table 19-7

HTN & Pregnancy

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Treatment of HTN in Pregnancy

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Cardioselective BB can be safely used in patients with Asthma or COPD and HTN (with compelling indication)

HTN & Reactive airway diseases

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noncoronary form of atherosclerotic vascular disease

Use ACEI BB can be problematic in PAD, but not

contraindicated in this group Use BB with α and β and blcoking activity

(carvedilol)

HTN in Patients with PAD

IV. Vascular Protection for Hypertensive Patients: Statins

In addition to current Canadian recommendations on management of dyslipidemia, statins are recommended in high-risk

hypertensive patients with established atherosclerotic disease or with at least 3 of the following criteria:

• Male

• Age 55 or older

• Smoking

• Total-C/HDL-C ratio of 6 mmol/L or higher

• Family History of Premature CV disease

• LVH

• ECG abnormalities

• Microalbuminuria or Proteinuria

ASCOT-LLA Lancet 2003;361:1149-58

IV. Vascular Protection for Hypertensive Patients: ASA

Consider low dose ASA

Caution should be exercised if BP is not controlled.

Secondary Prevention

Use of Aspirin in patients with HTN

Daily low dose aspirin is established in the secondary prevention of cardiovascular

disease

Aspirin in Patients with Diabetes and HTN

Low dose aspirin (75-162 mg) in Diabetic patients at increased CVD risk (10 year risk of CVD events over 10%) and not at increased risk for bleeding

(ACCF/AHA Class IIa, Level of Evidence: B) (ADA Level of Evidence: C)Low dose ASA maybe considered in diabetics at

intermediate CV risk

(ACCF/AHA Class IIb, Level of Evidence: C) (ADA Level of Evidence: E)

(ACCF/AHA Class III, Level of Evidence: C) (ADA Level of Evidence: C)

Do Not recommend low dose aspirin in patients at low risk. Potential Harm offset potential benefit

Circulation. 2010;121:2694-2701

High risk of bleeding

i. history of previous GI bleeding or

ii. PUD iii. concurrent use of

medications that increase bleeding risk, such as NSAIDS or warfarin

High CV riskAge M >50 , W >60+ one or more of:SmokingHypertensionDyslipidemiaFamHx of premature CVDalbuminuria

Moderate CV riskYounger patients+ one or more RFOlder patients with 10-year risk of 5-10%

Low CV riskAge M <50 yr , W <60 yr. With no major additionalCVD risk factors; 10-year CVD risk under 5%

Circulation. 2010;121:2694-2701

patients who are uncontrolled (failure to achieve goal BP of <140/90 mm Hg, or lower when indicated) with the use of three or more drugs.

Causes: Treatment

◦assure adequate diuretic therapy◦appropriate use of combination therapies◦use alternative antihypertensive agents when

needed

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Resistant HTN

Resistant HTN

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presence of very elevated BP, typically greater than 180/120 mm Hg.

HTN Urgencies are not associated with acute or immediately progressing target-organ injury

HTN emergencies are associated with acute or immediately progressing target-organ injury◦ encephalopathy, intracranial hemorrhage, acute left

ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, and eclampsia or severe hypertension during pregnancy.

Hypertensive Crisis

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Don’t correct rapidly Goal:

◦ gradual reduction in BP to prevent cerebrovascular accidents, MI, and acute kidney failure.

adjusting maintenance therapy, ◦ Add a new agent ◦ and/or by increasing the dose of a present medication.◦ Use oral agents over a period of several hours to several

days.◦ Reevaluate patient within and no later than 7 days

(preferably after 1 to 3 days)

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Hypertensive Urgency

Require hospitalization and administration of parenteral therapy

See table 19-11 Goal:

◦ a reduction in MAP of up to 25% within minutes to hours. ◦ If the patient is then stable, BP can be reduced toward

160/100 to 160/110 mm Hg within the next 2 to 6 hours. Rapid drops in BP may lead to end-organ ischemia or

infarction. ◦ If patients tolerate this reduction well, additional gradual

reductions toward goal BP values can be attempted after 24 to 48 hours.

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Hypertensive Emergency

Parenteral Antihypertensive Agents for Hypertensive Emergency

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Parenteral Antihypertensive Agents for Hypertensive Emergency

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50% of patients with newly diagnosed hypertension are continuing treatment at 1 year

Identify potential barriers to adherence◦ Misunderstanding of Condition◦ Denial of illness / Asymptomatic◦ Lack of patient involvement in care plan◦ Unexpected adverse effects of medicine◦ Too many f/u visits, lab requests◦ Emphasis on PCMH Goals / Objectives

HTN & Non-Adherence

• Assess adherence to pharmacological and non-pharmacological therapy at every visit

• Teach patients to take their pills on a regular schedule associated with a routine daily activity e.g. brushing teeth.

• Simplify medication regimens using long-acting once-daily dosing

• Utilize fixed-dose combination pills • Utilize unit-of-use packaging e.g. blister packaging

HTN & Non-Adherence

Replacing multiple pill antihypertensive combinations with single pill combinations!

Encourage greater patient responsibility/autonomy in regular monitoring of their blood pressure

Educate patients and patients' families about their disease/treatment regimens verbally and in writing

Use an interdisciplinary care approach coordinating with work-site health care givers and pharmacists if available

HTN & Non-Adherence

Efficacy◦BP: 2-4 weeks after initiation and each dose change◦Once BP goal is reached: monitor BP q 3-6 months◦Adherence at every visit, annual review of meds

Disease progression◦Periodically ,◦S&S of progressive hypertension-associated TOD

Toxicity:◦See Table 19-8

Monitoring Therapeutic Plan for patient with HTN

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Within 3 days of start of therapy and again at 1 week

Patient Education on:◦ Home BP measurement:

educate patient to measure during the early morning hours for most days and then at different times of the day on alternative days of the week

◦ Use of automated ambulatory BP monitoring Currently used in situations such as suspected white coat

hypertension.

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Monitoring Therapeutic Plan for patient with HTN

84

Review on the Individual

Antihypertensive agents

Subclass Drug (Brand Name) Usual Dose Range, mg/day Daily Frequency

Diuretics Thiazides

Chlorthalidone (Hygroton)

Hydrochlorothiazide (Esidrix, HydroDiuril,

Microzide, Oretic)Indapamide (Lozol)

Metolazone (Mykrox)Metolazone (Zaroxolyn)

6.25–25

12.5–25

1.25–2.50.5–1

2.5–10

1

1

111

LoopsBumetanide (Bumex)

Furosemide (Lasix)Torsemide (Demadex)

0.5–420–805–10

221

Diuretics

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Subclass Drug (Brand Name) Usual Dose Range, mg/day Daily Frequency

Potassium sparing

Amiloride (Midamor)Amiloride/

hydrochlorothiazide (Moduretic)Triamterene (Dyrenium)

Triamterene/ hydrochlorothiazide

(Dyazide)

5–105–10/50–100

50–100

37.5–75/25–50

1 or 21

1 or 2

1

Diuretics

Aldosterone Antagonists

Eplerenone (Inspra)Spironolactone

(Aldactone)Spironolactone/

hydrochlorothiazide (Aldactazide)

50–10025–50

25–50/25–50

1 or 21 or 2

1

Diuretics

86

Thiazides are more effective antihypertensives than loop diuretics in most patients

Loops are preferred in chronic kidney disease High dietary sodium intake can blunt their effect very effective in lowering BP when used in

combination with most other antihypertensives◦Additive/synergistic effect◦Counteract a compensatory increase in sodium and

fluid retention may be seen with antihypertensive agents.

Diuretics

87

use usual doses to avoid adverse metabolic effects

Ideally, dose in the morning if given once daily and in the morning and late afternoon when dosed twice daily to minimize risk of nocturnal diuresis

chlorthalidone is approximately 1.5 times as potent as HCTZ; have additional benefits in osteoporosis; may require additional monitoring in patients with a history of gout or hyponatremia

Diuretics

88

Diuretics SE Profile: Electrolyte imbalance:

◦Hypokalemia (more pronounced with loops)◦Hypomagnesemia◦Monitor closely especially in patients with

LVH, coronary disease, on digoxin therapy >> serious cardiac arrhythmias

Hypercalcemia (loops: hypocalcemia) sexual dysfunction

Diuretics

89

Metabolic disturbances: ◦Hyperuricemia If gout occur in a patient who requires

diuretic therapy, allopurinol can be given to prevent gout and will not compromise the antihypertensive effects of the diuretic

Diuretics

90

Hyperglycemia and dyslipidemia (more with TH-like)◦usually are transient and often inconsequential.

Potassium-sparing diuretics can cause hyperkalemia◦Avoid use with ACEI, ARB, direct renin inhibitor, K

supplements◦Eplerenone selective ARA, more hyperkalemia than

spironolactone

Diuretics

91

Can be used safely with most agents concurrent administration with lithium may result in

increased lithium serum concentrations and can predispose patients to lithium toxicity.

Diuretics Interactions

92

Patients on thiazide-type diuretic therapy have a higher incidence of developing type 2 diabetes

Rational: ◦ insulin utilization is linked to intracellular potassium.

Hypokalemia predispose to largest increases in glucose concentrations. The potassium cut point at which this relationship appears is when serum potassium is less than 4.0 mEq/L.

Thiazide induced Hyperglycemia

93

thiazide-type diuretics are NOT contraindicated in patients with diabetes, however , linicans should minimize hyperglycemia by:◦ use the lowest effective dose (e.g., hydrochlorothiazide

12.5 or 25 mg daily)◦ maintain serum potassium values between 4.0 and 5.0

mEq/L ◦ Encourage lifestyle modification.

Thiazide induced Hyperglycemia

Angiotensin Converting Enzyme Inhibitors (ACEI)

95

Has many evidence-based uses in patients with HTN and any compelling indications

Most ACEI can be dosed once daily in hypertension◦Sometime, twice daily dosing is needed to maintain

24-hour effects with enalapril, benazepril, moexipril, quinapril and ramipril.

well tolerated

Angiotensin Converting Enzyme Inhibitors

96

ACEI Side Effects Profile Hypotension:

starting dose should be reduced (almost by 50%) in patients at risk of hypotension (who are sodium or volume depleted, in heart failure exacerbation, very elderly, or on concurrent vasodilators or diuretics)

◦Start low and go slow

Angiotensin Converting Enzyme Inhibitors

97

Hyperkalemia◦Risk factors: CKD, concomitant K-sparing

diuretic, ARA, ARB, direct renin inhibitor and or K-supplements

◦Monitor K, creatinine values within 4 week, when starting or increasing the dose

Angiotensin Converting Enzyme Inhibitors

98

Acute kidney failure: ◦ Risk factors: pre-existing kidney disease severe bilateral

renal artery stenosis or severe stenosis in artery to solitary kidney

◦ Slowly titrate the dose and monitor kidney function◦ Anticipate small increase in serum creatinine (MOA of the

drug) If more than 35% increase in Cr from baseline (< 3mg/dl)

or absolute increase of >1 mg/dL yo may need to stop ACEI or reduce dose

Angiotensin Converting Enzyme Inhibitors

99

Angioedema include lip and tongue swelling and possibly

difficulty breathing. Serious cases, laryngeal edema and/or pulmonary symptoms

D/C ACEI and avoid future use May use ARB

TRANSCEND study

Angiotensin Converting Enzyme Inhibitors

100

Persistent cough◦In 20% of patients◦Inhibition of bradykinin

Pregnancy: major congenital malformations do not use in pregnancy or in patients with a

history of angioedema

Angiotensin Converting Enzyme Inhibitors

101

Angiotensin Receptor Blockers

102

Studies established that the CV event lowering benefits of ARB therapy are similar to ACE inhibitor therapy in hypertension. ◦ON-TARGET study ACEI-based vs. ARB-based therapy vs. ACEI+ARB No difference in 1 end point: CV death or

hospitalization for heart failure Combo regimen: no additional benefit and more

SE Comparable CV benefit as CCB-based therapy

Angiotensin Receptor Blockers

103

Lowest incidence of SE renal insufficiencyHyperkalemiaOrthostatic hypotension. Apply same precautions as with ACE

inhibitors should not be used in pregnancy

Angiotensin Receptor Blockers

104

Calcium Channel Blockers

105

Calcium Channel Blockers

106

Two subclasses of CCBs:◦DHP and non-DHP pharmacologically very different Antihypertensive effectiveness is similar Different pharmacodynamic effects.

◦DHP studied in the ALLHAT study◦Non-DHP◦have additional benefits in patients with atrial

tachyarrhythmia. Avoid in HF

Calcium Channel Blockers

107

CCB side effects profile DHP:

◦ Dizziness, flushing, headache, gingival hyperplasia, peripheral edema

◦ mood changes◦ various gastrointestinal complaints. ◦ Immediate release: reflex sympathetic stimulation

Non-DHP CCB:◦ anorexia, nausea, peripheral edema, and hypotension.

Verapamil causes constipation in about 7% of patients., less with diltiazem

Calcium Channel Blockers

108

drug interactions ◦CYP450 A3A4 (diltiazem, verapamil)◦Caution with: cyclosporine, digoxin,

lovastatin, simvastatin, tacrolimus, theophylline

Caution with non-DHP & BB: risk of heart block

CCB Hepatic metabolism inhibited by grape fruit juice (~ 1 qt/d= 4cups)

Calcium Channel Blockers

109

DHP:◦ Extended-release products are preferred for HTN◦ Immediate release DHP associated with an increased

incidence of adverse CV effects Not to be used in HTN

Non-DHP◦ SR formulation not AB rated by the FDA as interchangeable

on mg-per-mg basis Calan SR and Verelan

Different biopharmaceutical release mechanisms Clinical significant: none

CCB Formaulations

110

Rational: ◦ designed to target the circadian BP rhythm◦ blunting the early morning BP surge may result in greater

reductions in CV events than conventional products in the morning.

◦ Verapamil: Covera HS and Verelan PM, both dosed pm◦ Diltiazem: Cardizem LA, dosed am or pm

CONVINCE trial◦ Controlled ONset Verapamil Investigation of Cardiovascular

End-points No difference in CV events compared to a thiazide-type

diuretic–BB regimen

Chronotherapeutic formulations

111

Beta Blockers

112

Beta Blockers

113

Not a first line without compelling indications Compelling indications :

◦Post-MI, coronary artery disease◦left ventricular dysfunction and diabetes◦BB based therapy is not associated with lower CV

events Possible explanation: Most studies used atenolol atenolol was used as once daily instead of

twice daily (t1/2 is 6-7 hrs)

Beta Blockers

114

All BB provide a similar degree of BP lowering Different Pharmacodynamic properties:

◦Cardioselectivity◦ISA◦membrane-stabilizing effects

Cardioselective BB are preferred when treating HTN than nonselective BB◦cardioselectivity is a dose-dependent phenomenon

Beta Blockers

115

BB with ISA◦ do not appear to reduce CV events◦ resting heart rate, CO, and peripheral blood flow are not

reduced◦ may increase risk post-MI or in those with coronary artery

disease. ◦ rarely used

All -blockers exert a membrane-stabilizing action on cardiac cells when large doses are given◦ Of value when BB are used as an antiarrhythmic agent.

Beta Blockers

116

BB Pharmacokinetic differences ◦first-pass metabolism◦route of elimination (renal vs. hepatic)◦ lipophilicity (more CNS SE)◦serum half-lives.

Beta Blockers

117

BB Side Effect Profile◦Bradycardia◦2nd , 3rd heart block◦Acute HF: if initial dose is high◦Avoid abrupt cessation abrupt discontinuation may present as

tachycardia, sweating, and generalized malaise in addition to increased BP.

Taper gradually over 1 to 2 weeks

Beta Blockers

118

Metabolic SE of BB◦May increase serum cholesterol and glucose

values◦Transient , little clinical significance.

erectile dysfunction Cold extremities aggravate intermittent claudication or

Raynaud phenomenon

Beta Blockers

119

The first oral direct renin inhibitor Block RAAS at point of activation

Aliskiren (Tekturna ®)

120Nature Reviews Drug Discovery 7, 399-410 (May 2008)

Approved in 2007 as mono and combination therapy no long-term studies evaluating CV event reduction and

significant drug cost compared to older generic agents with outcome data

Available products: single drug or combination with:◦ amlodipine◦ HCTZ◦ Valsartan: no longer marketed◦ triple combination tab with HCTZ and amlodipine

Aliskiren (Tekturna ®)

Dose: 150-300 mg once daily◦ High fat meal decrease absorption

Side effects: ◦Similar to ACEI and ARB

Consider avoiding in women during childbearing years◦Can cause diarrhea◦Monitor K and serum Cr after initiation or titration of

dose◦Caution: angioedema

Aliskiren (Tekturna ®)

ALTITUDE trial:◦ Trial was terminated early◦ Aliskiren added to ACEI or ARB therapy in patients with type 2

diabetes mellitus and renal impairment compared with a placebo add-on

◦ An increase in nonfatal stroke, renal complications,◦ hyperkalemia, and hypotension and no apparent benefits among

patients randomized to aliskiren group FDA Black Box Warning:

◦Use in combination with ACEI or ARB in patients with diabetes or renal impairment (GFR<60 ml/min) should be avoided.

Aliskiren (Tekturna ®)

(Curr Drug Saf. 2012 Feb;7(1):76-85)