Evidence Based Treatment of Hypertension

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
Lab Lecture

Learning Objectives Demonstrate an understanding of the different roles of pharmacology, pathophysiology, and evidence based medicine as they apply to patient therapy Demonstrate understanding of pathological disorders caused by chronic, poorly controlled hypertension Identify signs and symptoms of end-organ damage due to hypertension 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 Classify patients by JNC-7 Hypertension levels Assign blood pressure goals according to AHA 2007 Scientific Statement for patients based on comorbidities Select most appropriate therapy for patients based on Evidence Based Medicine Compelling Indications 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 Clinical 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

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 Hypertension
Sympathetic Activation Peripheral Resistance Cardiac Output HR Stroke Volume Renin AT II Aldosterone Blood Pressure Plasma Adapted from APhA’s Completed Review for Pharmacy. Gourley, DR. 2004

Pathophysiology of Hypertension(HTN)
Increased Sympathetic Activation Excessive vascular volume Activation of the Renin Anginotensin Aldosterone System 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
Chronic Kidney Disease Peripheral Vascular Disease Retinopathy HTN Whenever working with a patient, check for signs of end organ damage (e.g. Retinopathy, Heart sounds, Chest Pain, unilateral weakness, Edema, increased urniation) Run baseline labs (Chem 7, EKG, Lipid Panel, Uric Acid) Ischemic Heart Disease Cerebrovascular Disease Heart Failure

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 Hypertensive Crisis
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

Hypertension and Cardiovascular Disease
A sustained 12mmHg reduction over 10 years prevents 1 death for 11 patients treated (Haxby Lecture) Benefits of HTN treatment are so profound and well documented, no large placebo control trials have been done in over 10 years, as it is viewed as unethical (Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008) High Normal = /85-89mmHg Normal = /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
2 Agent Initial Therapy 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

From JNC-7 to 2007 AHA Guidelines
Past Medical History Blood Pressure Goal Framingham Risk Score <10% Primary Prevention <140/90 mmHg >10% Diabetes Melitus Chronic Kidney Disease <130/80 mmHg CAD Risk Equivalents CAD Left Ventricular Dysfunction <120/80 mmHg Adapted From Saseen, JJ. Essential Hypertension. Applied Therapeutics: The Clinical Use of Drugs 10th edition. 2008

Framingham Risk Factors and CAD Equivalents
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 from Center for Disease Control and Prevention Data from Dr Haxby’s Spring Smoking Lecture

Caffeine Caffeine

JNC-7 Recommendations by Hypertension Stage

JNC-7 Recommendations by Compelling Indication

2007 AHA Scientific Statement Recommendations
First Line Therapy Past Medical History Blood Pressure Goal Framingham Risk Score <10% ACEI/ARB or CCB or Thiazide Diuretic Primary Prevention <140/90 mmHg >10% ACEI/ARB or CCB or Thiazide Diuretic Diabetes Melitus Chronic Kidney Disease <130/80 mmHg CAD Risk Equivalents BB‡ and ACEI/ARB CAD (ACEI/ARB or BB) And Diuretic And Aldosterone Antagonist And Hydralazine/Isosorbide Dinitrate¥ Left Ventricular Dysfunction <120/80 mmHg Adapted From Saseen, JJ. Essential Hypertnesion. Applied Therapeutics: The Clinical Use of Drugs 10th edition and Rosendorff, C., et. Al. AHA Scientific Statement. Treatment of Hypertnesion in the Prevention and Management of Ischemic Heart Disease. Circulation. 2007;115: ‡ 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:

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 Action
Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure Aldosterone HR Stroke Volume Plasma Volume AT II Renin

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

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

Potassium Sparing Diuretics– Mechanism of Action
Mild Diuretic Effects Usually used for synergistics effects Na↑ K↓

ACE Inhibitors – Mechanism of Action
Sympathetic Activation Peripheral Resistance Cardiac Output Blood Pressure ACEI do not completely block conversion of AT-1 to AT-2 Aldosterone HR Stroke Volume Plasma Volume AT II ACE Renin

Angiotensin Receptor Blockers– Mechanism of Action

Renin Inhibitors – Mechanism of Action

Beta Blockers – Mechanism of Action

Non-DHP CCB– Mechanism of Action

Alpha Blockers – Mechanism of Action

DHP CCB– Mechanism of Action

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

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 Thiazide CCB Supplemental OR (Per Dr. Haxby’s Lecture) For Combination Therapy, Thiazides are still the Gold standard for uncomplicated monotherapy ACEI/BB Foundation Adapted from Williams, B, Poulter, NR, Morris, JP, et al. British Hypertension Society Guidelines for Hypertension Management 2004 (BHS-IV). BMJ 2004;328;

Drug Interactions Physiological Pharmacological Metabolic
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
Don’t Panic 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

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
Chronic Kidney Disease Diabetes Peripheral Vascular Disease Retinopathy HTN Ischemic Heart Disease Cerebrovascular Disease Heart Failure

Evidence Based Treatment of Hypertension

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