Evidence Based Treatment of Hypertension

Harleen Singh, Pharm.D.Ted D. Williams, Pharm.D. Candidate

OSU/OHSU College of Pharmacy

P4 Year – Investing in your Education

Lecture

Lab

Learning Objectives1. Demonstrate an understanding of the different roles of pharmacology,

pathophysiology, and evidence based medicine as they apply to patient therapy

2. Demonstrate understanding of pathological disorders caused by chronic, poorly controlled hypertension

3. Identify signs and symptoms of end-organ damage due to hypertension4. Demonstrate an understanding of sites of action and most likely side effects of

various antihypertensive drug classes and differences between drugs in the same class

5. Classify patients by JNC-7 Hypertension levels6. Assign blood pressure goals according to AHA 2007 Scientific Statement for

patients based on comorbidities7. Select most appropriate therapy for patients based on Evidence Based

Medicine Compelling Indications8. Apply outcomes of landmark hypertension studies to selecting patient therapy

The Road Ahead

• Evidence Based Medicine (EBM) Primer• Hypertension Defined, Epidemiology, Complications• Goals of Hypertension Therapy• Hypertension Treatment Guidelines• Non-Pharmacological Treaments of Hypertension • Pharmacology Review– By Drug Class– Assessing Drug Interactions

• EBM for pharmacological treatment selection

Evidence Based Medicine

• Evidence-based medicine (EBM)– EBM is the conscientious, explicit, and judicious

use of the current best evidence in making decisions about the care of individual patients.(Sackett 1998)

Pathophysiology, Pharmacology and EBM

• Pathophysiology suggests where we can intervene to improve outcomes

• Pharmacology helps predict likely targets– Therapeutic Effects– Adverse Effects

• Clinical Trials show what happens when we treat 10,000 patients– Evidence Based Medicine lives here

Types of Significance

• Statistical Significance– Can we detect any difference

• Clinical Significance– Do we care if there is a difference

• Patient Significance– Blood Glucose level differences with Thiazide

Diuretics are significantly higher vs. placebo– Increase in Blood Glucose 3-5mg/dL in non-diabetics– Is this clinically significant?

EBM In Real Life

• Question for PharmD: Recommend a therapy for a patient on 25mg HCTZ QDay with BP 140/95

• Answer from PharmD: “Continue HCTZ 25mg Q Day and add Lisinopril 10mg Q Day, titrating to 40mg Q Day”

• Response: “Why not increase HCTZ to 50mg Q Day. Micromedex says the max daily dose is 100mg”

• PharmD: ???

JNC-7

• The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

• Gold Standard EBM in Hypertension diagnosis and treatment

Case

More Cases

Hypertension Defined

• Elevated Blood Pressure (BP)– Systolic Blood Pressure (SBP) >=140mmHg– Diastolic Blood Pressure (DBP) >=90mmHg

Epidemiology of Hypertension

• Approximately 50 million people in the U.S. have hypertension.

• The incidence of hypertension increases steadily with age and prevalence is higher in blacks than in whites. Prevalence exceeds 60% in people over age 60.

• There is a strong correlation between blood pressure and cardiovascular morbidity and mortality.– Systolic BP has a stronger correlation than diastolic

BP, but both are important

Epidemiology of Hypertension

• The higher the pressure, the greater the risk of myocardial infarction, angina, stroke, heart failure, renal failure, peripheral vascular disease and retinopathy.– For each 20mm increase in SBP or 10mm increase in DBP over

115/75, risk doubles– Complication rates increase with each additional CVD risk factor

that is present– Hypertension accounts for 2/3 of strokes and about 25% of MIs

• Preventing and controlling hypertension is a major strategy for reducing CVD morbidity and mortality.

• While 70% of hypertensives are aware of their condition and 59% are being treated; only 34% are controlled.

Determinants of Blood Pressure

• Arterial blood pressure is generated by the interplay of cardiac output and total peripheral resistance: BP = CO x TPR

• It reaches a peak during cardiac contraction (systolic pressure) and a nadir at the end of cardiac relaxation (diastolic pressure).

• Blood pressure is measured in millimeters of mercury and recorded as systolic (SBP) over diastolic pressure (DBP).

• The difference between the systolic and the diastolic pressure is the pulse pressure (PP)

• Mean arterial pressure (MAP) = 1/3 PP + DBP.

Pathophysiology of HypertensionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Adapted from APhA’s Completed Review for Pharmacy. Gourley, DR. 2004

Pathophysiology of Hypertension(HTN)

1. Increased Sympathetic Activation2. Excessive vascular volume3. Activation of the Renin Anginotensin

Aldosterone System4. Peripheral Resistance

Causes of Hypertension

• Idiopathic– 90-95% of cases have no known etiology

• Secondary– Renal Insufficiency– Coarcation of the aorta– Primary Aldosteronism– Thyroid/parathyroid disease– Cushing’s Syndrome– Pheochromocytoma– Sleep Apnea– Increased Intracranial pressure

• Look for secondary causes, but don’t expect to find them

Hypertension as a Risk Factor

HTN

RETINOPATHY

HEART FAILURE

ISCHEMIC HEART

DISEASECEREBROVASCULAR

DISEASE

PERIPHERAL VASCULAR

DISEASE

CHRONIC KIDNEY DISEASE

Hypertension as a Risk Factor

• Hypertension is a primary risk factor for multiple co-morbidities– Ischemic Heart Disease (IHD)

• aka Carotid Artery Disease (CAD), Coronary Heart Disease(CHD)• Myocardial Infarction (MI)• Angina

– Heart Failure (HF)– Left Ventricular Hypertrophy or Dysfunction (LVH, LVD)– Cerebrovascular Disease

• Stroke• Transient Ischemic Attack (TIA)

– Chronic Kidney Disease (CKD)– Retinopathy

Types of Hypertension

• Chronic– What we will focus on today and what we will call

Hypertension• Hypertensive Crisis– Hypertensive Emergency– Hypertensive Urgency– Dr Marrs will discuss this in detail in subsequent

lectures

Hypertensive Crisis

• Less than 1% of all hypertensives will ever have a hypertensive crisis.

• Hypertensive crisis is defined as a diastolic pressure above 120mm Hg.

• There are 2 types of hypertensive crisis: – hypertensive emergency – hypertensive urgency

Goals of Hypertensive Therapy

• Long Term• Short Term

Long Term Goals of Hypertension Therapy

• Direct Measures– Reduced Mortality– Reduced incidence of end organ damage• Cardiovascular• Cerebrovascular• Renal• Retinopathy

– Trailing indicators

Short Term Goals of Hypertension Therapy

• Surrogate markers– Blood Pressure– Leading indicator

• Why is blood pressure a good surrogate marker?

Hypertension and Ischemic Heart Disease

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

Hypertension and Stroke

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

Hypertension and Cardiovascular Disease

• High Normal = 130-139/85-89mmHg• Normal = 120-129/80-84mmHg• Optimal <120/<80mmHg The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

2004

JNC-7 Hypertension Classifications

DBP = Diastolic Blood Pressure, SBP = Systolic Blood Pressure*Treatment should be determined by the highest blood pressure‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80mmHg

JNC-7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

2 Agent Initial Therapy

From JNC-7 to 2007 AHA Guidelines

Primary Prevention

Past Medical History Blood Pressure Goal

Diabetes Melitus

Chronic Kidney Disease

CAD

Left Ventricular Dysfunction

FraminghamRisk Score <140/90 mmHg

<130/80 mmHg

<10%

>10%

<120/80 mmHg

Adapted From Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10 th edition. 2008

CAD Risk Equivalents

Framingham Risk Factors and CAD Equivalents

• Framingham Risk Factors– Age > 45– Total Cholesterol– Smoking– HDL Cholesterol– Systolic Blood Pressure– See ATP III Guidelines for scoring algorithm

• CAD Equivalents– Ischemic Stroke– Transient Ischemic Attack– Peripheral Arterial Disease– Abdominal Aortic Aneurysm

Therapy• Therapeutic Lifestyle Changes (TLC)• Pharmacological Therapy

Therapeutic Lifestyle Changes vs. Pharmacotherapy

Therapeutic Intervention Approximate SBP Reduction

Weight Reduction (5-10% or 10kg) 5-20mmHg

DASH Diet (Low sodium, low fat) 8-14mmHg

Single Antihypertensive 10mmHg (10 over 5 rule)30 minutes exercise most days 4-9mmHg

Dietary Sodium Reduction 2-8mmHg

Reduce alcohol to <=2 drinks/day 2-4mmHg

Adapted From: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

Weight Reduction

Dash Diet

30 Minutes of Exercise

Sodium Restriction Trial• 412 subjects randomized

to typical American diet (control) or DASH diet and to three different sodium levels for 30 days with a 2 week run in period– High 3.5g– Intermediate 2.3g

(Recommended DASH)– Low 1.2g

• Typical American diet is 4,100 mg per day for men and 2,750 for women (JNC-7)Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary

Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10

Sodium Restriction Trial

Sacks, et al. Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. NEJM 2001(1);344:3-10

Smoking

• Smoking– In the first year

after quitting, excess risk of a cardiovascular event is cut in half, and after 5-15 years, the rate approaches that of a never smoker

Annual Smoking Related Deaths 1995-1999 from Center for Disease Control and Prevention

Caffeine

• Caffeine

JNC-7 Recommendations by Hypertension Stage

JNC-7 Recommendations by Compelling Indication

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004

2007 AHA Scientific Statement Recommendations

Primary Prevention

Past Medical History Blood Pressure Goal

Diabetes Melitus

Chronic Kidney Disease

CAD

Left Ventricular Dysfunction

FraminghamRisk Score <140/90 mmHg

<130/80 mmHg

<10%

>10%

<120/80 mmHg

Adapted From Saseen, JJ. Essential Hypertnesion. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008 and Rosendorff, C., et. Al. AHA Scientific Statement. Treatment of Hypertnesion in the Prevention and Management of Ischemic Heart Disease. Circulation. 2007;115:2761-2788.

First Line Therapy

ACEI/ARB or CCB or Thiazide Diuretic

ACEI/ARB or CCB or Thiazide Diuretic

CAD Risk Equivalents

BB‡ and ACEI/ARB

(ACEI/ARB or BB) And DiureticAnd Aldosterone Antagonist And Hydralazine/Isosorbide Dinitrate¥

‡ Only use BB in patients who are hemodynamically stable¥ African American

2007 AHA Scientific Statement Recommendations

Rosendorff, C., et. Al. AHA Scientific Statement. Treatment of Hypertnesion in the Prevention and Management of Ischemic Heart Disease. Circulation. 2007;115:2761-2788.

Antihypertensive Therapies• Volume Management

– Loop Diuretics – Thiazide Diuretics– Potassium Sparing Diuretics

• Including Aldosterone Antagonists (Aldo Ant)

• RAAS Agents– Angiotensin Converting Enzyme Inhibitors (ACEI)– Angiotensin II Receptor Blockers (ARB)– Renin Inhibitors

• Direct Cardiac Agents– Beta Blockers (BB)– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)

• Vasodilators– Dihydropyridine Calcium Channel Blockers (DHP CCB)– Alpha 1 Antagonists

Antihypertensive Therapies• Volume Management

– Loop Diuretics – Thiazide Diuretics– Potassium Sparing Diuretics

• Including Aldosterone Antagonists (Aldo Ant)

• RAAS Agents– Angiotensin Converting Enzyme Inhibitors (ACEI)– Angiotensin II Receptor Blockers (ARB)– Renin Inhibitors

• Direct Cardiac Agents– Beta Blockers (BB)– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)

• Vasodilators– Dihydropyridine Calcium Channel Blockers (DHP CCB)– Alpha 1 Antagonists

Loop Diuretics – Mechanism of ActionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Loop Diuretics – Mechanism of Action

• Act mainly in ascending loop of Henle to decrease sodium reabsorption

• Action is shorter but more intense than other diuretics

• Preferred for edema vs. BP management

Na↑ Ca↑Mg↑ K↑

Thiazide Diuretics – Mechanism of Action

Sympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Thiazide Diuretics– Mechanism of Action

• Increase urinary excretion

• Works at the distal convoluted renal tubules

• Increase urinary excretion of potassium

• Additional MOA– May cause

peripheral vasodilation, but this is unclear

Na Cl↑+ K↑

Potassium Sparing Diuretics – Mechanism of Action

Sympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Potassium Sparing Diuretics– Mechanism of Action

• Mild Diuretic Effects

• Usually used for synergistics effects

Na↑ K↓

Antihypertensive Therapies• Volume Management

– Loop Diuretics – Thiazide Diuretics– Potassium Sparing Diuretics

• Including Aldosterone Antagonists (Aldo Ant)

• RAAS Agents– Angiotensin Converting Enzyme Inhibitors (ACEI)– Angiotensin II Receptor Blockers (ARB)– Renin Inhibitors

• Direct Cardiac Agents– Beta Blockers (BB)– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)

• Vasodilators– Dihydropyridine Calcium Channel Blockers (DHP CCB)– Alpha 1 Antagonists

ACE Inhibitors – Mechanism of ActionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

ACE

Angiotensin Receptor Blockers– Mechanism of Action

Sympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Renin Inhibitors – Mechanism of ActionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Antihypertensive Therapies• Volume Management

– Loop Diuretics – Thiazide Diuretics– Potassium Sparing Diuretics

• Including Aldosterone Antagonists (Aldo Ant)

• RAAS Agents– Angiotensin Converting Enzyme Inhibitors (ACEI)– Angiotensin II Receptor Blockers (ARB)– Renin Inhibitors

• Direct Cardiac Agents– Beta Blockers (BB)– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)

• Vasodilators– Dihydropyridine Calcium Channel Blockers (DHP CCB)– Alpha 1 Antagonists

Beta Blockers – Mechanism of ActionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Non-DHP CCB– Mechanism of ActionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Antihypertensive Therapies• Volume Management

– Loop Diuretics – Thiazide Diuretics– Potassium Sparing Diuretics

• Including Aldosterone Antagonists (Aldo Ant)

• RAAS Agents– Angiotensin Converting Enzyme Inhibitors (ACEI)– Angiotensin II Receptor Blockers (ARB)– Renin Inhibitors

• Direct Cardiac Agents– Beta Blockers (BB)– Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)

• Vasodilators– Dihydropyridine Calcium Channel Blockers (DHP CCB)– Alpha 1 Antagonists

Alpha Blockers – Mechanism of ActionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

DHP CCB– Mechanism of ActionSympathetic Activation

Peripheral Resistance

Cardiac Output

HR StrokeVolume

Renin

AT II

Aldosterone

Blood Pressure

PlasmaVolume

Other CVD Risk Reducing Agents

• Aspirin• Statins

Combination Therapy – Stepped, Sequential, Concurrent

• Stepped Care– Select one agent initially and titrate to effect– If BP control is not achieved, add-on another agent– Standard approach

• Sequential– Select one agent initially and titrate to effect– If BP control is not achieved, switch to another agent– Use when medication is poorly tolerated or sub-optimal

efficacy• Concurrent

– Start two or more agents simultaneously and titrate in parallel– Reserved for special needs patient (e.g. JNC-7 Stage 2 HTN)

Combination Therapy Recommendations

• 2 Drug ACEI/BB + (Diuretic or CCB)• 3 Drug ACEI/BB + Diuretic + CCB• Remember, don’t combine CCB and BB without extreme

caution and compelling indications

ACEI/BB

Thiazide CCBOR

Adapted from Williams, B, Poulter, NR, Morris, JP, et al. British Hypertension Society Guidelines for Hypertension Management 2004 (BHS-IV). BMJ 2004;328;634-640

Foundation

Supplemental

Drug Interactions

• Physiological– e.g. Non-DHP CCB and BB

• Pharmacological– e.g. Non-Selective BB and Beta Agonists in COPD

• Metabolic– e.g. Statins (3A4 Substrates) and Non-DHP CCB

(3A4 Inhibitors)

Drug Interaction Dictionary• Corticosteroids• Anorectics (e.g., phenylporpanolamine, sibutramine, amphetamines)• Cocaine• Buproprion plus nicotine replacement• Cyclosporine, tacrolimus• Decongestants• Erythropoeitin and analogues• Licorice• Ma huang, ephedra, bitter orange• Monoamine oxidase inhibitors• Nonsteroidal anti-inflammatory drugs/ Cox 2 inhibitors• Oral contraceptives• Thyroid hormone excess• Venlafaxine• Anabolic steroids

Don’t Panic

Approach to Drug Interactions

• Consider site of action and molecular structure– NSAIDs • Prostaglandin Synthesis Inhibitor

– Lithium (Na)• Competitive

– Steroids (Na)• Aldosterone Analogs

Drug Interaction Dictionary Revisited

• Corticosteroids• Anorectics (e.g., phenylporpanolamine, sibutramine, amphetamines)• Cocaine• Buproprion plus nicotine replacement• Cyclosporine, tacrolimus• Decongestants• Erythropoeitin and analogues• Licorice• Ma huang, ephedra, bitter orange• Monoamine oxidase inhibitors• Nonsteroidal anti-inflammatory drugs/ Cox 2 inhibitors• Oral contraceptives• Thyroid hormone excess• Venlafaxine• Anabolic steroids

Compelling Indications

HTN

RETINOPATHY

HEART FAILURE

ISCHEMIC HEART

DISEASECEREBROVASCULAR

DISEASE

PERIPHERAL VASCULAR

DISEASE

CHRONIC KIDNEY DISEASE

DIABETES