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Hypertension: Pharmacotherapeutic Principals

Treating Patients with Hypertension

Robert J. Straka, Pharm.D. FCCPProfessor

University of Minnesota

College of Pharmacy

Minneapolis, Minnesota

[email protected]

Pharmacotherapy AssignmentHomework assignment:

1) Register for use of “theheart.org” (great resource for CV related issues) http://www.theheart.org/

2) Familiarize yourself with the American Heart Association website for retrieving scientific statements and guidelines:

a) Go to http://www.heart.org/HEARTORG/b) Upper Bar: click on “Healthcare/Research”c) Upper left: “Statements and Guidelines”d) View by “topic” or “chronological” and scroll down to “Hypertension”e) Retrieve a PDF version of “Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease:”(Rosendorff et al)) (You can just store the PDF for later reference) (Hint: the May 2007 )

Learning Objectives:At the end of the presentation, learners should be able to:

1) Describe several key facts about the epidemiology and pathophysiology of hypertension

2) Describe and explain the goals and overall approach to managing patients with hypertension with an emphasis on pharmacotherapeutic issues

3) Demonstrate how to apply approaches recommended by JNC 7 and 2007 AHA statement on hypertension to a clinical case

4) Apply your knowledge of salient features of pharmacotherapeutic agents commonly used to treat patients with hypertension and be able to develop a rationale for drug selection for specific patient cases using evidenced-based guidance where possible Adapted from JNC 7 Slide Deck. Available at: http://www.nhlbi.nih.gov. (JNC8 expected Release Fall 2011

¥ some 25% US population have prehypertension and 25% of Americans have BP >140/90) from Rosendorf Circ 2007

JNC 7 Guidelines for Hypertension (HTN)

• Goal: To reduce Cardiovascular (CV) morbidity and mortality through prevention and management of HTN

• JNC 7 Guidelines (2003)

100 160Hypertension, Stage 2

90-99140-159Hypertension, Stage 1

80-89120-139Prehypertension¥

< 80< 120Normal

DBP (mm Hg)SBP (mm Hg)Category

Classification of Blood Pressure

Vasan, RS, et al. N Engl J Med 2001;345:1291-7

Framingham Study - CV Events and BP

“Figure for Concept Only: Note: These are older Definitions”Framingham Study – Spectrum of CV Events and BP

Optimal <120 and <80, Normal <130 and <85, High normal 130-139 or 85-89 (note: JNC VI not JNC 7 definitions)

Age-Adjusted Relative Risk for CHD DeathMultiple Risk Factor Intervention Trial Circ 1999;100:354

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Estimated 10Estimated 10--Year CVD risk in 50Year CVD risk in 50--5454--yearyear--old adults according to levels of various risk factors old adults according to levels of various risk factors (Framingham Heart Study).(Framingham Heart Study).Source: DSource: D’’Agostino et al., Circulation. 2008;117:743Agostino et al., Circulation. 2008;117:743--753.753.

A B C DAge 50-54 50-54 50-54 50-54HDL Cholesterol, mg/dL 45-49 45-49 35-34 35-34Total Cholesterol (mg/dL) 160-199 200-239 200-239 200-239Systolic BP mm/Hg, no treat. 120-29 130-139 130-139 130-139Smoker No No No YesDiabetes No No Yes Yesmm Hg = millimeters of mercury. mg/dL = milligrams per deciliter of blood

7.911.2

21.6

4.57.3

30+

15.9

24.8

0

5

10

15

20

25

30

35

A B C D

Est

imat

ed 1

0-Y

ear

Rat

e%

Men

Women

34

21

17

1312

23

12

810

6

18

11

9

66

17

88

6

4

14

56

33

142+142+

125125--131131

<182<182182182--202202

203203--220220221221--244244

Cholesterol QuintileCholesterol Quintile(mg/dL)(mg/dL)

Systolic BP Quintile Systolic BP Quintile (mm Hg)(mm Hg)<118<118

118118--124124

132132--141141

CHD Deaths/10,000 PatientCHD Deaths/10,000 Patient--YearsYears

245+245+

NeatonNeaton et al. et al. Arch Intern MedArch Intern Med. 1992;152:56. 1992;152:56--64.64.

MRFIT: Impact of Elevated SBP and Total Cholesterol on CHD Mortality (N=316,099)

Target Organ Damage in Hypertension

HYPERTENSION

LVH= Left ventricular hypertrophy, CHF= Coronary Heart Disease, CHF= Chronic Heart Failure Adapted from JNC V. Arch Intern Med. 1993;1563:154.

Stroke

Retinopathy

LVHCHDCHF

Renalimpairment

Decreased arterialcompliance

Extent of awareness, treatment and control of high blood pressure by race/ethnicity (NHANES : 2005-2006)

Source: NCHS and NHLBI

70.178.8

69.1

45.4

79.0

46.1

74.7

82.3

46.5

67.6

52.1

35.2

010

203040

506070

8090

Awareness Treatment Controlled

Per

cen

t o

f P

op

ula

tio

n W

ith

Hyp

erte

nsi

on

Total Population NH Whites NH Blacks Mexican Americans

Challenge?

Factors Contributing to HypertensionEtiology of hypertension is rarely known

There are many physiological factors in that may play a role in hypertension such as abnormalities in

- neural mechanisms (CNS or peripheral auto-regulation problems)

- disturbances in electrolytes (Na+, Ca++) and

- naturetic hormone regulation (RAAS)

These provide some rationale for the use of drugs eg. alpha-receptor blockers, beta-blockers, diuretics and ACE inhibitors

Problem: Of those that have hypertension, only 35% achieve goal BP

Opportunity: Hypertension is a major risk factor for morbidity and mortality due to cardiovascular disease (CVD)

JNC - 7

The Seventh Report

of the

Joint National Committee on Prevention, Detection, Evaluation, and Treatment of

High Blood PressureThe JNC 7 report. Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572

Web Site

http://www.nhlbi.nih.gov/guidelines/hypertension/index.htm

JNC 8 report expected release data Fall 2010

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JNC 7 Highlights

• For patients older than 50 years, SBP >140 mm Hg is a more important CVD risk factor than DBP

• Patients with pre-hypertension require health-promoting Therapeutic Lifestyle Changes (TLC) to prevent CVD (low Na+ diet, exercise, smoking cessation etc.) These may lower SBP by up to 2-4 mmHg each

• Thiazide-type diuretics should be used (either alone or in combination) for most patients with uncomplicated hypertension

• Most patients (likely all diabetics) will require 2 or more antihypertensive agents to reach their goal blood pressure

• If BP is >20/10 mm Hg above goal, consider initiating therapy with 2 agents, one of which should usually be a thiazide-type diuretic

The JNC 7 report. JAMA. 2003;289:2560-2572.The JNC 7 report. Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572 ¥ some 25% US population have prehypertension and 25% of Americans have BP >140/90

from Rosendorff Circ 2007

JNC 7 Guidelines for Hypertension (HTN)

• Goal: To reduce Cardiovascular (CV) morbidity and mortality through prevention and management of HTN

• JNC 7 Guidelines (2003)

100 160Hypertension, Stage 2

90-99140-159Hypertension, Stage 1

80-89120-139Prehypertension¥

< 80< 120Normal

DBP (mm Hg)SBP (mm Hg)Category

Classification of Blood Pressure

Lowering BP Is Imperative in Reducing Cardiovascular Risk

Myocardial Infarction Stroke¥ Heart Failure

20%-25%

35%-40%

>50%

In clinical trials, antihypertensive therapy has been associated with reductions in:

The JNC 7 report. Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572Neal B et al. Lancet. 2000;356:1955-1964.¥ Stroke is main benefit attributed to drug therapy of “very old” (>85yo)

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

Patient Evaluation

Evaluation of patients with documented HTN has three objectives

1. Assess lifestyle and identify other CV risk factors or concomitant disorders that affects prognosis and guides treatment

2. Reveal identifiable causes of high BP

3. Assess the presence or absence of target organ damage and CVD*(Cardiovascular Disease)

The JNC 7 report. JAMA. 2003;289:2560-2572.

Major CVD Risk Factors: JNC 7

Hypertension*

Cigarette smoking

Physical inactivity

Obesity (body mass index ³30 kg/m2)*

Dyslipidemia*

Diabetes mellitus*

Microalbuminuria or estimated GFR <60 mL/min

Age (>55 years for men, >65 for women)

Family history of premature CVD (men aged <55 or women aged <65 years)

*Components of the metabolic syndrome*Components of the metabolic syndromeItalicized = modifiableItalicized = modifiable

Identifiable Causes and Target Organ Damage

Identifiable Causes:

• Sleep apnea, drug induced, chronic kidney disease, primary aldosteronism, renovascular disease, chronic steroid therapy andCushing’s syndrome, pheochromocytoma, coarctation of the aorta, thyroid or parathyroid disease.

Target Organ Damage:

- Heart: (LVH, Angina or MI, revascularization, Heart failure)

- Brain: (Stroke or TIA)

- Chronic Kidney Disease (reduced Clcr)

- Peripheral Arterial Disease

- Retinopathy The JNC 7 report. JAMA. 2003;289:2560-2572

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Laboratory Tests

• Routine Tests:

– ECG (looking for ischemic heart disease)

– UA (urine analysis looking for protein= renal damage)

– Blood glucose, and hematocrit

– Serum K+, creatinine, or estimated GFR and Ca++

– Fasting lipid profile, (HDL, LDL and TG)

Optional Tests:

– Measurement of Urinary albumin excretion or albumin/creatinine ratio

– More extensive testing for identifiable causes not generally indicated unless BP control is not achieved

The JNC 7 report. Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572

Goals of Therapy

• Reduce CVD and renal morbidity and mortality

• Treat to BP < 140/90 mmHg or BP < 130/80 mmHg in patients with diabetes or chronic kidney disease

• Achieve SBP goal especially in persons >50 years of age


JNC 7: Lifestyle Modification

2-4 mmHgModeration of alcohol consumption

4-9 mmHgPhysical activity

2-8 mmHgDietary sodium reduction

8-14 mmHgAdopt DASH eating plan

5-20 mmHg/10Kg wt lossWeight Reduction

Approximate SBP reduction (range)Modification

.


JNC 7 Algorithm for Treatment***


JNC 7: Compelling Indications for Individual Drug Classes

THIAZ, ACEIRecurrent stroke prevention

ACEI, ARBChronic kidney disease

THIAZ, BB, ACEI, ARB, CCBDiabetes

THIAZ, BB, ACEI, CCBHigh CVD risk

BB, ACEI, ALDO ANTPost-myocardial infarction

THIAZ, BB, ACEI, ARB, ALDO ANTHeart failure

Recommended Drug ClassesCompelling Indication

.The JNC 7 report. Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572

Compelling Indications for Individual Drug Classes: JNC 7

Recommended Clinical Trial BasisCompelling Indication

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM

DIUR, BB, ACE, CCB

BB, ACEI, ALDO ANT

DIUR, BB, ACEI, ARB, ALDO-ANT

High CAD risk

Post-myocardialinfarction

Heart failure

Adapted from Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572

JNC

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Recurrent stroke prevention

Chronic kidney disease

Diabetes

Compelling Indication

DIUR, ACEI

ACEI, ARB

DIUR, BB, ACE, ARB, CCB

Compelling Indications for Individual Drug Classes: JNC 7

PROGRESS

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

NKF-ADA Guideline,UKPDS, ALLHAT

Adapted from Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572.

Recommended Clinical Trial Basis

Landmark Studies Supporting the Guidelines

• ALLHAT, ANBP2, VALUE ASCOT-BPL

• MERIT-HF, VALHFT, CHARM

• LIFE, LIFE Substudy

• HOPE , Micro-HOPE, HOPE_ABM vs Office

• IDNT RENAAL

• AASK

• Others: HYVET, ACCOMPLISH, ONTARGET

Case 1:

• Mrs. Smith is a nonsmoking 46 year old with type 2 diabetes. She had her BP measured several times with a representative average reading of 144/102 mmHg.

• Other information on her at this time includes a waist circumference of 34”, Fasting lipid panel result of Total Cholesterol of 215mg/dL, HDL-C of 56mg/dL, LDL-C of 115mg/dL and TG of 220mg/dL with a fasting plasma glucose of 84mg/dL and no other medical problems.

• Current medications: metformin 500mg twice a day (for diabetes)

1) Which of the following best describes her classification of hypertension according to the JNC 7 guidelines?

Norm

al

Pre

hyper

tensi

on

Hyp

erte

nsion S

tage

1

Hyp

ertensio

n Sta

ge 2

Hyp

erte

nsion S

tage

3

0% 0% 0%0%0%

1. Normal

2. Prehypertension

3. Hypertension Stage 1



According to JNC 7, what would be her goal BP, knowing all you know at this time?

<140/

90 mm

Hg

<140/

80 mm

Hg

<130/

90 mm

Hg

<130/

80 mm

Hg

<120/

80 mm

Hg

0% 0% 0%0%0%

1. <140/90 mmHg

2. <140/80 mmHg

3. <130/90 mmHg

4. <130/80 mmHg

5. <120/80 mmHg

Overall Approach to Hypertension Management

• Clinical Trials have limitations: Eg. heterogeneous of populations, use of multiple drugs (some not inherently obvious combinations), lack of dose escalation

• General Recommendations: Both JNC 7 guidelines and the AHA statement on managing hypertensive patients for the prevention and management of IHD, are based on evidence, pharmacology, pathophysiology and co-morbidities.

• Each integrate knowledge of pharmacology and evidence to provide a structure and context to drug selection.

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Treatment of Hypertension in the Prevention and Management of IHD:

AHA Scientific Statement Rosendorff et al Circulation 2007;115:2761-2788 2770

This scientific statement has several sections

a. General Recommendations (Know these and table)

b. Management of HTN in Pts. With ACS-UA and NSTEMI

c. Management of HTN in Pts. With ACS- STEMI

d. Management of HTN in Pts. With HF of Ischemic Origin

There are themes that are based in evidence and/or practical pharmacologic or pathophysiologic principles

Recommendations follow the AHA/ACC classification scheme

(HTN=Hypertension, IHD= ischemic heart disease, ACS= acute coronary syndromes, UA= unstable angina, STEMI= ST segment elevation Myocardial Infarction, HF= heart failure)

I IIa IIb III

AHA Format for Classification of Recommendations and Levels of Evidence

Intervention is useful and effective

Evidence conflicts/opinions differ but leans towards efficacy

Evidence conflicts/opinions differ but leans against efficacy

Intervention is not useful/effective and may be harmful

.

AA-- Data derived from large multiple randomized clinical trials or Data derived from large multiple randomized clinical trials or metameta--analysis analysis BB-- Single randomized trial or nonrandomized studiesSingle randomized trial or nonrandomized studiesCC-- Expert Opinion, Consensus based on case studies or standard of Expert Opinion, Consensus based on case studies or standard of carecare

Treatment of Hypertension in the Prevention and Management of IHD: General Recommendations

AHA Scientific Statement Rosendorff et al Circulation 2007;115:2761-2788 2770

1) For the primary prevention of CAD in hypertension, aggressive BP lowering is appropriate, with a target BP of <130/80 mm Hg in individuals with any of the following: DM; chronic renal disease; CAD; CAD risk equivalents; carotid artery disease; peripheral arterial disease; AAA; and for high-risk patients, defined as those with a 10-year Framingham risk score of >10%; and

– a target BP of <140/90 mm Hg in individuals with none of the above

– (Class IIa; Level of Evidence B)

Treatment of Hypertension in the Prevention and Management of IHD

Rosendorff et al Circulation 2007;115:2761-2788 2770

2) In patients with an elevated DBP and CAD with evidence of myocardial ischemia, the BP should be lowered slowly, and caution is advised in inducing falls of DBP below 60 mm Hg if the patient has DM or is over 60 years.

• In older hypertensive individuals with wide pulse pressures, lowering SBP may cause very low DBP values (<60 mm Hg). The clinician should carefully assess for any untoward signs or symptoms, especially those due to myocardial ischemia.

• In the very old, (> 80), antihypertensive therapy is effective in reducing stroke risk, but evidence for a reduction in coronary events is less certain (Class IIa; Level of Evidence C)

Treatment of Hypertension in the Prevention and Management of IHD

Rosendorff et al Circulation 2007;115:2761-2788 2770

3)The choice of drugs remains controversial. There is a general consensus that the amount of BP reduction, rather than the choice of antihypertensive drug, is the major determinant of reduction of cardiovascular risk;however, there is sufficient evidence in the comparative clinical trials to support the use of an ACE inhibitor (or ARB), CCB, or thiazide diuretic as first-line therapy, supplemented by a second drug if BP control is notachieved by monotherapy.

• Most patients will require >2 drugs to reach goal, and when the BP is >20/10 mm Hg above goal, 2 drugs should usually be used from the outset.

• In the asymptomatic post-MI patient, a beta-blocker is a more appropriate choice for secondary prevention for at least 6 months after the infarction and is the drug of first choice if the patient has angina pectoris.

• (Class I; Level of Evidence A)Goal here means 140/90mmHg

ß-Blocker (if patient is hemodynamically stable) and ACEI or

ARB

<130/80 Stable angina (SA) or

UA/NSTEMI or STEMI

ACEI or ARB or CCB or thiazide diuretic or combination

<130/80 High CAD risk*

Any effective¥ antihypertensive drug or combination

<140/90General CAD prevention

Specific Drug Indications

(Lifestyle Modifications for all)

BP Target, mm Hg

Area of Concern

Simplified AHA Statement

Rosendorff Circulation 2007***

*DM, CKD, known CAD or CAD equiv., or >10% Framingham score¥ = effective antihypertensive (ACE, (or ARB), CCBA or thiazide

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•If ß-blocker contraindicated, or if side effects occur, can substitute diltiazem or verapamil (but not if bradycardiaor LVD is present)

•Can add dihydropyridine CCB (not diltiazem or verapamil) to ß-blocker

•A thiazide diuretic can be added for BP control

ß-Blocker (if patient is hemodynamically stable) and

ACEI or ARB

<130/80 Stable angina or UA/NSTE

MI or STEMI

If SBP > 160 mm Hg or DBP > 100 mm Hg, then start with 2 drugs

*DM, CKD, known CAD or CAD equiv., or >10% Framingham score

ACEI or ARB or CCB orthiazide diuretic or

combination


If SBP >160 mm Hg or DBP > 100 mm Hg, then start with 2 drugs

Any effective antihypertensive drug or

combination

<140/90General CAD

prevention

Comments Specific Drug Indications


BP Target, mm Hg

Area of Concern

Simplified AHA Statement (No LVD)

AHA Statement Rosendorff Circulation 2007***

Contraindicated: verapamil, diltiazem, clonidine, moxonidine, -blockers

¶ severe HF(NYHA III or IV, or LV<40% and clinical HF)

ACEI or ARB and ß-blocker andaldosterone antagonist¶ and thiazide

or loop diuretic andhydralazine/ISDN (blacks)

<120/80LVD

•If ß-blocker contraindicated, or if side effects occur, can substitute diltiazem or verapamil (but not if bradycardia or LVD is present)



ß-Blocker (if patient is hemodynamically stable) and ACEI

or ARB

<130/80 Stable angina or

UA/NSTEMI or STEMI






Any effective antihypertensive drug or combination

<140/90General CAD

prevention



BP Target, mm Hg

Area of Concern

Simplified: (Simplified for Confirmed CAD)



¶ severe HF (NYHA III or IV, or LV<40% and clinical HF)

ACEI or ARB and ß-blocker andaldosterone antagonist¶ and thiazide or

loop diuretic and hydralazine/ISDN (blacks)

<120/80LVD




ß-Blocker (if patient is hemodynamicallystable) and ACEI or ARB

<130/80 STEMI





<130/80 UA/NSTEMI




ß-Blocker and ACEI or ARB <130/80 Stable angina





If SBP >160 mm Hg or DBP > 100 mm Hg, then start with 2 drugs Any effective antihypertensive drug or combination




BP Target, mm Hg

Area of Concern


Antihypertensive Drug Classes

• Diuretics (hydrochlorothiazide)

• Adrenergic inhibitors (-blockers, -blockers, central -agonists, combined - blockers) eg. metoprolol, doxazocin, clonidine, carvedilol

• Calcium Channel Blockers (eg. diltiazem, almlodipine)

• ACE inhibitors (eg. lisinopril)

• Angiotensin II receptor antagonists (ARBs) (irbesartan)

• Others (vasoldilators eg. hydralazine, renin inhibitor: aliskiren)

• Drug combinations

Diuretics• Well studied: Class of agents for HTN and in Heart Failure

• Inexpensive: Low acquisition cost

• Evidence: proven benefit lowering morbidity/mortality

• MOA: Decrease PVR in the long term (blocks Na+ re-absorption)

• Monitor for: Hypokalemia (low potassium), hyperuracemia, hyperglycemia, hypercalcemia, lipid effects, gynecomastia(spirionlactone)

• Which Agent? (Thiazides or Loops)

• ClCr > 30 ml/min thiazide (all probably work equally well)

• ClCr < 30 ml/min loop diuretics or combination

-Blockers for Hypertension

• Mechanism: reduce cardiac work by negative inotropic, negative chronotropic and hypotensive (central and renin blocking) effects

• Pharmacologic Issues: Diverse group: some primarily block Beta-1receptors, some also have alpha-blocking activity

• Monitor: SE’s are extension of pharmacologic effects, bradycardia, hypotension, diabetes (block signs and symptoms of hypoglycemia) reactive airway disease, adverse lipid effects

• Comments: Useful with select co-morbidities eg. ischemic heart disease, (angina, myocardial infarction), heart failure, however not favorable vs. other options from contemporary guidelines (Rosendorff2007) (see Meta-analysis: Lindholm Lancet 2005;345:1545-53 )

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ß-Blocker (if patient is hemodynamically stable) and ACEI or

ARB

<130/80 Stable angina (SA) or

UA/NSTEMI or STEMI



Any effective¥ antihypertensive drug or combination


Specific Drug Indications


BP Target, mm Hg

Area of Concern

Simplified AHA Statement

Rosendorff Circulation 2007***

*DM, CKD, known CAD or CAD equiv., or >10% Framingham score¥ = effective antihypertensive (ACE, (or ARB), CCBA or thiazide

•If ß-blocker contraindicated, or if side effects occur, can substitute diltiazem or verapamil (but not if bradycardiaor LVD is present)



ß-Blocker (if patient is hemodynamically stable) and

ACEI or ARB

<130/80 Stable angina or UA/NSTE

MI or STEMI



ACEI or ARB or CCB orthiazide diuretic or

combination



Any effective antihypertensive drug or

combination

<140/90General CAD

prevention



BP Target, mm Hg

Area of Concern

Simplified AHA Statement (No LVD)


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¶ severe HF(NYHA III or IV, or LV<40% and clinical HF)

ACEI or ARB and ß-blocker andaldosterone antagonist¶ and thiazide

or loop diuretic andhydralazine/ISDN (blacks)

<120/80LVD




ß-Blocker (if patient is hemodynamically stable) and ACEI

or ARB

<130/80 Stable angina or

UA/NSTEMI or STEMI






Any effective antihypertensive drug or combination

<140/90General CAD

prevention



BP Target, mm Hg

Area of Concern

Simplified: (Simplified for Confirmed CAD)



¶ severe HF (NYHA III or IV, or LV<40% and clinical HF)

ACEI or ARB and ß-blocker andaldosterone antagonist¶ and thiazide or

loop diuretic and hydralazine/ISDN (blacks)

<120/80LVD





<130/80 STEMI





<130/80 UA/NSTEMI




ß-Blocker and ACEI or ARB <130/80 Stable angina





If SBP >160 mm Hg or DBP > 100 mm Hg, then start with 2 drugs Any effective antihypertensive drug or combination




BP Target, mm Hg

Area of Concern


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Beta-Blocking Agents

Non-Selective Selective*

NadololPropranololTimolol

PindololCarteololPenbutolol

AtenololMetoprololEsmololBetaxololBisoprolol

Acebutolol Labetolol (Carvedilol Nebivolol*

- ISA + ISA+ ISA- ISA

WithVasodilatingProperties

*Cardioselective for blocking Beta-1ISA = Intrinsic Sympathomimetic ActivityNO= Nitrous Oxide

Calcium Channel Blocking Agents (CCBA’s) for Hypertension

• Mechanism: reduce cardiac work by negative chronotropic(heart rate), negative inotropic (contractility) and systemic vasodilation (relax sm. muscles of arterioles)

• Pharmacologic Issues: relative effects on conduction system, negative inotropism, vasodilatation

• Monitor: HR, BP, ECG

• Issues: Edema with higher doses of amlodipine and possible verapamil, CYP3A4 inhibition of verapamil/diltiazem?

CCBA’S Chemical Classification

• Benzothiazepines– Diltiazem (Cardizem™, Dilacor™, Tiazac™ , Others)

• Phenylalkylamines– Verapamil (Calan™, Isoptin™, Covera-HS™, others)

• Dihydropyridines– Amlodipine (Norvasc™) Nifedipine (Procardia™, Adalat™)

– Nicardipine (Cardene™) Felodipine (Plendil™)

– Isradipine (DynaCirc™) Nimodipine (Nimotop™)

– Bepridil (Vascor™)

– Nisoldipine (Sular™)

ACE Inhibitors for Hypertension

Mechanism: Block conversion of Angiotensin I to angiotensin II and blocks breakdown of bradykinin (vasodilator)

Side Effects:- Hypotension (monitor BP)- Renal Insufficiency (monitor Scr)- Potassium retention (monitor K)- Cough- Rare: angioedema

Conclusions:- ACE I's useful to treat patients with HTN, Heart Failure,

post Myocardial Infarction and diabetic nephropathy

ACE Inhibitors for Hypertension

Mechanism:Block conversion of Angiotensin I to angiotensin II and

blocks breakdown of bradykinin (vasodilator)

Side Effects:- Hypotension (monitor BP)- Renal Insufficiency (monitor Scr)- Potassium retention (monitor K)- Cough- Rare: angioedema

Monitor/Issues: Key option for diabetics, patients with heart failure, myocardial infarction

ANGIOTENSINOGEN

ANGIOTENSIN I

ANGIOTENSIN II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Glu-Ser

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin Converting

Enzyme

Renin

AT1 Receptor

RENIN INHIBITORS

ACE INHIBITORS

AII ANTAGONISTS

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Renin Angiotensin Aldosterone System (RAAS) ACE Inhibitors

ANGIOTENSINOGEN

Angiotensin I

ANGIOTENSIN II Inactivepeptides

Renin

ACE

Non-renin

Non-ACE

Bradykinin

ACEI

AT1 AT2 ATn

AT-Angiotensin Receptor

Angiotensin Receptor Blockers (ARBs)

ANGIOTENSINOGEN

Angiotensin I

ANGIOTENSIN II Inactivepeptides

Renin

ACE

Non-renin

Non-ACE

Bradykinin

AT1

AT2(?) ATn

ARBsAT1 receptor stimulates:Vasoconstriction, Cell growth, Na+ retention, Sympathetic activation

ReninInhibitor*

*Aliskiren= renin inhibitor

Angiotensin II Receptor Blockers (ARBs)

• Similar anti-HTN efficacy to ACE inhibitors and atenolol (perhaps less SE’s and D/C rates)

• Not inferior to ACE’s for outcomes (ONTARGET NEJM 2008)

• Advantages may be in reduced incidence of cough and angioedema (vs. ACE inhibitors) although angioedema has been reported

• Apparently no effects on lipids, fasting glucose although have asignificant uricosuric effect

• Hyperkalemia can occur to comparable level as with ACE inhibitors

Classification of Angiotensin II Receptors

Sensitive to blockade by:Losartan, Valsartan, etc.

AT2AT1

Sensitive to blockade by:CGP 42112A, PD123177

•Vasoconstriction•Aldosterone Release•Cardiac Inotropic Effect•Vasopressin Release•Increase SNS Activity•Decrease Renin Release•Renal Na+ & H2O Re-absorption•Cell Growth & Proliferation

•Vasodilation•Antiproliferation•Apoptosis•Bradykinin Release•Nitric Oxide Release

Angiotensin II Receptor Blockers (ARBs)• Losartan (Cozaar® Merck, 25 + 50 mg tabs qd-bid)

• Valsartan (Diovan®,Novartis, 80 and 160 mg caps qd)

• Irbesartan (Avapro® BMS, 150-300mg/d tabs qd)

• Telmisartan (Micardis® Boehring Ing, Glaxo Welcome, 20-80mg tabs qd )

• Candesartan (Atacand ®,Astra Merck, 4, 8,16,32mg tabs (qd-bid))

• All of available agents are approved for hypertension

– Hyzaar® is losartan 50 mg/HCT 12.5 mg tablet

– Diovan HCT ® is valsartan + HCT 80/12.5 or 160/12.5 capsules

– Avalide ® is irbesartan + HCT 12.5 or 25mg tablets

Cough: ARBs vs Enalapril

Percent of patients experiencing cough16

12

8

4

0

16

12

8

4

0

16

12

8

4

00.7

4.33.0

15.1*13.1*

2.5

Pat

ient

s (%

)

Pat

ient

s (%

)

Pat

ient

s (%

)

Enalapriln = 61

Irbesartann = 121

Enalapriln = 199

Losartann = 200

Enalapriln = 60

Valsartann = 137

* P < .01

Larochelle P, et al. Am J Hypertens.1997;10:131A.

Tikikanen I, et al.J Hypertens. 1995;13:1343.

Holwerda NJ, et al.J Hypertens. 1996;14:1147.

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10

Irbesartan Safety Profile: Comparable to Placebo

20

15

10

5

0

16.7

Pat

ient

s (%

)

Headache

Placebo (n = 641)

Irbesartan (n = 1,965)

Data on file.

Selected adverse events often associated with antihypertensive therapyoccurring in more than 1% of patients in placebo-controlled trials

12.3

6.6 6.65.0 4.9

2.7 2.8 2.82.1 2.3

1.5

Musculo-skeletal

pain

Dizziness Cough Nausea/vomiting

Edema

Aliskiren (Tekturna®)

• Oral direct plasma renin inhibitor which decreases plasma renin activity by inhibiting conversion of angiotensinogen to Ang 1 approved for HTN (alone or in combination)

• PK: Absorption unknown, bioavailability is poor (~3%) Cmaxwithin 1-3 hrs, AUC decreased by 70% with high fat meals, 25% eliminated unchanged, some CYP3A4 metabolism

• Issues: Contraindicated in pregnancy, angioedema potential, cough > PL, but < ACE inhibitors but early

• Dose: 150mg/once daily up to 300mg/d

• Role: TBD (combos with HCT, Almodipine and Valsartan)

-Blockers in Patients With Hypertension

•• Agents: Agents: DoxazosinDoxazosin ((CarduraCardura®®), ), PrazosinPrazosin ((MinipressMinipress®®), ), TerazosinTerazosin ((HytrinHytrin®®), ), TamsulosinTamsulosin((FlomaxFlomax®®))

•• AdvantagesAdvantages

• Useful in patients with dyslipidemia: neutral or beneficial effect on lipids

• Useful in patients with hypertension and benign prostatic hypertrophy

•• DisadvantagesDisadvantages

• Can produce 1st dose syncope

• Common SEs (5-20%): Dizziness, headache, lethargy, palpitations

• Orthostatic hypotension can occur

• Early termination of doxazocin arm of ALLHAT due to negative outcome (higher HF, stroke, CVD risk) of doxazocin vs. chlorthalidone (JAMA 2000:283;1967-75)

Centrally acting -Agonists in Patients With Hypertension

Agents: : Clonidine (Clonidine (CatapressCatapress®®), ), GuanabenzGuanabenz , , GuanfacineGuanfacine, Methyldopa , Methyldopa ((AldometAldomet®®))

Advantages

- Clonidine : very quick onset and useful for hypertensive urgencies

- Clonidine : as a patch is applied once a week improving adherence

- Methyldopa is a useful antihypertensive during pregnancy

Disadvantages

- Many frequent (5-40%) SEs limit the use of these agents (e.g. Dry mouth, drowsiness, dizziness, constipation, weakness, nausea & vomiting, agitation, orthostatic hypotension)

- Abrupt withdrawal of therapy results in a rapid (24-48hr) rebound hypertension

Peripherally Acting Adrenergic BlockersAgents: : Guanadrel, Guanethidine, Reserpine

Advantages

-- Reserpine is generally well tolerated at low doses

- Low Cost

Disadvantages

- Common SEs (5-40%) for Guanadrel, GuanethidineGuanadrel, Guanethidine : significant orthostatic hypotension, syncope, diarrhea, drowsiness, fatigue,decreased ejaculation, peripheral edema, nasal stuffiness, cough, palpitations, SOB, leg cramps

- Reserpine SEs: Nasal congestion, activation of PUD Avoid in PUD patients. Possible dose related depression Avoid in patients with depression history

Direct Vasodilators

Agents: : Hydralazine, MinoxidilHydralazine, Minoxidil

Advantages

- Both are potent vasodilators

- Hydralazine IV is a safe choice for eclampsia

- Minoxidil could be added to a regimen in case of a resistant hypertension

Disadvantages

-- Minoxidil SEs: Hirsutism, transient ECG (T wave) changes

- Hydralazine common SEs: Headache, nausea / vomiting, diarrhea,

- Reflex tachycardia and RAAS activation for both

Straka

11

Additional Considerations in Antihypertensive Drug Choices

• Potential favorable effects:

– Thiazide diuretics useful in slowing demineralization in osteoporosis

– BBs useful in the treatment of atrial tachyarrhythmias/fibrillation, migraine, thyrotoxicosis(short term), essential tremor, or periopertative HTN

– CCBs useful in Raynaud’s syndrome and certain arrhythmias

– Alpha-blockers useful in prostatism.

Additional Considerations in Antihypertensive Drug Choices

• Potential unfavorable effects:

– Thiazide diuretics should be used cautiously in gout (use ARBs) or history of significant hyponatremia

– BBs should be generally avoided in patients with asthma, reactive airway disease or second or third-degree heart block

– ACEIs and ARBs are contraindicated in pregnant women or those likely to be come pregnant

– ACEIs should not be used in individuals with a history of angioedema

– Aldosterone antagonists and K-sparing diuretics can cause hyperkalemia

Treatment Diabetes:Diabetes Care 29;S4-S42:2006

• Initial drug therapy for those with a blood pressure >140/90 should be with a drug class demonstrated to reduce CVD events in patients with diabetes (ACE inhibitors, ARBs, -blockers, diuretics, calcium channel blockers). (A)

– All patients with diabetes and hypertension should be treated with a regimen that includes either and ACE inhibitor or ARB (E)

Hypertension Management in Adults with Diabetes (Diabetes Care, Hypertension Management in Adults with Diabetes (Diabetes Care, VolVol 29 S429 S4--S42, S42, Supplements Jan 2006)Supplements Jan 2006)

Treatment Diabetes:Diabetes Care 29;S4-S42:2006 con’t

• If ACE inhibitors or ARBs are used, monitor renal function and serum potassium levels. (E)

• While there are no adequate head-to-head comparisons of ACE inhibitors and ARBs, (in 2008 there is*) there is clinical trial support for each of the following statements:

– In patients with type 1 diabetes with hypertension and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (A)

– In patients with type 2 diabetes, hypertension, and microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria. (A)

– In those with type 2 diabetes, hypertension, macroalbuminuria (>300 mg/day), and renal insufficiency, an ARB should be strongly considered. (A)

Hypertension Management in Adults with Diabetes (Diabetes Care, Hypertension Management in Adults with Diabetes (Diabetes Care, Vol 29, S4Vol 29, S4--S42, Jan 2006)S42, Jan 2006)

* ONTARGET: NEJM 2008;358:1547-1559

Selected Side Effects With Hypertensive Medications

• Cough (common)

• Angioedema (rare)

• Hyperkalemia (rare)

• Rash (rare)

• Loss of taste (rare)

ACE Inhibitors

• Angioedema (very rare)

• Hyperkalemia

• Edema of the ankle

• Flushing

• Headache

• Gingival hypertrophy

• Bronchospasm

• Bradycardia

• Heart failure

• Mask insulin-induced hypoglycemia

•Impaired peripheral

circulation

• Insomnia

• Fatigue

• decr. Exercise tolerance

•Dyslipidemic †

ARBsCalcium Channel Blockers*Beta Blockers

*Dihydropyridine†Except agents with intrinsic sympathomimetic activity JNC VI. Arch Intern Med. 1997;157:2413-2446.

No. of antihypertensive agents1 2 3 4

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.1. UKPDS 38. BMJ. 1998;317:703-713.2. Estacio RO et al. Am J Cardiol. 1998;82:9R-14R.3. Lazarus JM et al. Hypertension. 1997;29:641-650.4. Hansson L et al. Lancet. 1998;351:1755-1762.

5. Kusek JW et al. Control Clin Trials. 1996;16:40S-46S.6. Lewis EJ et al. N Engl J Med. 2001;345:851-860.7. ALLHAT. JAMA. 2002;288:2998-3007.

Multiple Antihypertensive Agents Are Often Needed to Achieve Target BP

SBP 140/DBP 90ALLHAT7

SBP 135/DBP 85IDNT6

•MAP 92AASK5

DBP 80HOT4

MAP 92MDRD3

DBP <75ABCD2

DBP <85 UKPDS1

•Target BP (mm Hg)•Trial

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12

Combination Drug Therapy

Rational for the use of combination agents:

1. Maximize antihypertensive efficacyutilizing different pharmacologic agentsblock opposing actions of each entity

2. Minimize side effectsblock the predictable side effects from the single entity buy using dual therapy

3. Rarely cost more than individual agents (reduces co-pay)4. Improves compliance (less # of drugs to take)

Follow-up and Monitoring

• Patients should return for follow-up and adjustment of medications until the BP goal is reached (~4-6 weeks)

• More frequent visits for stage 2 HTN or with complicating comorbid conditions

• Serum K+ and SCr monitored 1-2 times per year

• After BP at goal and stable, follow-up at 3-6 month intervals

• Comorbidities, such as heart failure, diabetes etc. and the needfor laboratory tests influence the frequency of visits

Essentials of Hypertension:Summary

• Fundamental basis for aggressive management of blood pressure is established

• Guidelines for selection of drug classes must be considered as guide for most patients

• Special populations (eg. Diabetics) may require specific approaches with multiple drugs

• Too many patients are less than optimally managed for hypertension and other risk factors for CVD

#1 According to JNC 7, what stage of HTN does AB have at this time?

No B

P pro

blem

Pre

hypertensi

ve

Norm

al

Hig

h Norm

al

Sta

ge 1

Sta

ge 2

Sta

ge 3

0% 0% 0% 0%0%0%0%

1. No BP problem2. Prehypertensive3. Normal4. High Normal5. Stage 16. Stage 27. Stage 3

http://www.courses.ahc.umn.edu/pharmacy/5822/htncase1.html

#4 Once the diagnosis of hypertension is established, what would be the most appropriate treatment option (after TLC)?

Meto

prolo

l 50m

g po b

id

Lis

inopril

5 m

g po q

am

Clo

nidin

e 0.

1mg p

o bid

HCT 1

2.5m

g po q

am

Lis

inopril

5m

g po q

am ..

.

0% 0% 0%0%0%

1. Metoprolol 50mg po bid

2. Lisinopril 5 mg po qam

3. Clonidine 0.1mg po bid

4. HCT 12.5mg po qam

5. Lisinopril 5mg po qam plus HCT 12.5 mg po qam

#6 What is the BP goal given the conditions in this case?

<140/

90 mm

Hg

<140/

80 mm

Hg

<130/

90 mm

Hg

<130/

80 mm

Hg

<120/

80 mm

Hg

0% 0% 0%0%0%

1. <140/90 mmHg

2. <140/80 mmHg

3. <130/90 mmHg

4. <130/80 mmHg

5. <120/80 mmHg

Straka

13

#7 From Case One; (http://www.courses.ahc.umn.edu/pharmacy/5822/htncase1.html) what would you calculate AB’s Framingham risk score to be based on the Table? How about based on the regression program?

14%19%

11%10%

30%

0% 0% 0%0%0%

1. 14%

2. 19%

3. 11%

4. 10%

5. 30%

Sample Quiz Question: Based on your review of the VALUE, ASCOT-BPLA and HYVET studies of hypertension, which of the following statement(s) are correct?

VALUE s

upports th

e i...

At l

east one o

f these s

...

Tre

ating h

ypertensio

n i...

All

of the

above a

re c

or...

0% 0%0%0%

1. VALUE supports the importance of prompt BP control in high risk patients

2. At least one of these studies support the notion that an beta-blocker- thiazide based therapy may be inferior to a CCBA-ACE regimen for some clinical endpoints

3. Treating hypertension in the 80+yr old patients is beneficial

4. All of the above are correct statements about these trials

Sample Quiz Question: Based on your review of the JNC 7 and Rosendorff guidelines, which of the following statement(s) are correct?

Both

are

consis

tent w

rt...

Both

are

consis

tent w

rt...

They d

iffer i

n their

use ..

All

of the

above a

re c

or...

0% 0%0%0%

1. Both are consistent wrt their call for 2 or more drugs for individuals with BP levels much higher than target values

2. Both are consistent wrt their call for considering a target of <130/80mmHg for patients with diabetes and chronic kidney disease

3. They differ in their use of the 10-year Framingham risk calculator in terms of identifying target BP goals

4. All of the above are correct statements about these guidelines

1

Hypothesis: In hypertensive patients at high cardiovascular risk,

for the same level of blood pressure control, valsartan will be

more effective than amlodipine in reducing cardiac morbidity and

mortality

Methods: multi-country, randomized, DB, parallel-group

comparison of valsartan vs amlodipine based* Tx in high risk

patients (n=15,245) >50yo followed up for ~4.2 yrs

Results: BP reduced by both treatments but amlodipine based

regimen lowered BP more-earlier in the study. Primary

Composite endpoint HR 1.04 (p=0.49)

Valsartan Antihypertensive Long-Term Use Evaluation

•*Based = HCT “could” be added as needed as well as other agents. •Julius S et al. Lancet. June 2004;363.

VALUE: Systolic Blood Pressure in Study

Julius S et al. Lancet. June 2004;363.

Valsartan (N= 7649)

Amlodipine (N = 7596)

135

140

145

150

155

mm

Hg

Months

Sitting SBP by Time and Treatment Group

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66

01.02.03.04.0

1 24 48

mm

Hg

2 3 4 6 12 18 30 36 42 54 60 66Months

5.0Difference in SBP Between Valsartan and Amlodipine

–1.0

(or final visit)

(or final visit)

VALUE: Primary Composite Cardiac Endpoint

14

12

10

8

6

4

2

0

Time (months)0 6 12 18 24 30 36 42 48 54 60 66

Pro

por

tion

of

Pat

ien

ts

Wit

h F

irst

Eve

nt

(%) Valsartan-based regimen

Amlodipine-based regimen

HR = 1.03; 95% CI = 0.94–1.14; P = 0.49


Number at risk

Valsartan

Amlodipine 7596

7649

7469

7459

7424

7407

7267

7250

7117

7085

6772

6732

6955

6906

6576

6536

5959

5911

3725

3765

1474

1474

6391

6349

1o SCD, Fatal MI, death during or post PCI or CABG, HF hospitalizations, NFMI,)

Time (months)Number at riskValsartan

Amlodipine 7596

7649

7497

7499

7458

7458

7332

7319

7205

7177

6905

6853

7065

7016

6727

6680

6141

6078

3840

3864

1532

1520

6562

6504

Pro

por

tion

of

Pat

ien

ts

Wit

h F

irst

Eve

nt

(%)

7

6

5

4

3

2

1

0

VALUE: Fatal and Non-FatalMyocardial Infarction 2o endpoint

0 6 12 18 24 30 36 42 48 54 60 66

Valsartan-based regimenAmlodipine-based regimen

HR = 1.19; 95% CI = 1.02–1.38; P = 0.02


VALUE: Incidence of NewVALUE: Incidence of New--onset Diabetes onset Diabetes 2o

endpoint

New

-On

set

Dia

bete

s (%

of

pati

ents

in

trea

tmen

t gr

oup)


0

2

4

6

8

10

12

14

Valsartan-based Regimen

(n = 5094)

Amlodipine-based Regimen

(n = 5074)

13.1%

16.4%

23% Risk Reduction With Valsartan

16

18

P < 0.0001

VALUE: Outcome and SBP Differencesat Specific Time Periods: Myocardial Infarction

Time Interval(months)

Overall study

Study end

1.0 2.00.5

Myocardial InfarctionOdds Ratios and 95% CIs

SBP(mmHg)

1.41.61.82.0

3.8

1.7

2.2

2.3

4.00.25

36–4824–3612–246–12

0–33–6

Favours amlodipineFavours valsartan


2

VALUE: TolerabilityVALUE: Tolerability

*With an incidence >3% and a difference between treatment groups >1%.†Reported as serious.

P Value(%)(%)

0.045

<0.0001<0.0001<0.0001

2.02.4Atrial Fibrillation†

1.01.7Syncope†

6.23.5Hypokalaemia*

Prespecified adverse events

6.49.3Angina Pectoris*3.14.4Angina Pectoris†

6.13.2Oedema Other*

6.88.8Diarrhoea*Additional common adverse events

14.513.4

12.915.2Headache14.316.5Dizziness32.914.9Peripheral Oedema

Amlodipine Valsartan

Data on file. Novartis Pharmaceuticals.

Discontinuations due to AE

<0.0001<0.0001<0.0001

0.1197<0.0001<0.0001

<0.0001

Summary: Good BP control was achieved with both treatment

regimens, but BP decrease in the amlodipine group was more pronounced, particularly early in the trialDespite blood pressure differences, the primary composite cardiac endpoint was not different between the treatment groupsInterpretation: No difference in main outcomes, however unequal reductions in BP may account for differences between groups in cause-specific outcomes. Prompt BP control is important in high risk hypertensives.

VALUE


1

1

• Expected mean follow-up: 5 years

• Primary end point: nonfatal MI and fatal CHD

The AngloThe Anglo--Scandinavian Cardiac Outcomes Scandinavian Cardiac Outcomes Trial (ASCOT): Study DesignTrial (ASCOT): Study Design

Adapted from Sever PS et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147.

n = 5168Atorvastatin

10 mg

n = 5137Placebo

n = 10,305Randomized, Double-Blind

RandomizedN = 19,342

Amlodipine perindoprildoxazosin GITs

Moderate-risk hypertensive patients

Eligible for lipid lowering Not eligible for lipid lowering

Atenolol bendroflumethiazidedoxazosin GITs

ASCOT BPLA

ASCOTLLA

2

ASCOTASCOT--BPLA (2004): BPLA (2004): Study Stopped Early for EfficacyStudy Stopped Early for Efficacy

• Goal of trial: compare 2 antihypertensive treatment strategies for the prevention of CHD events in hypertensive patients

• Planned follow-up: 5 years

• Trial stopped: October 2004

• Primary Objective: Compare the effect on NFMI and fatal CHD of the standard antihypertensive regimen (beta-blocker ± diuretic) with a more contemporary regimen (CCB ± ACE inhibitor)

ASCOT termination release [press release]. Available at: www.ascotstudy.org. Accessed December 14, 2004.

3

amlodipine 5-10 mg atenolol 50-100 mg

perindopril 4-8 mgbendroflumethiazide-K

1.25-2.5 mg

doxazosin GITS 4-8 mg

add

add add

additional drugs, eg, moxonidine/spironolactone

add

Treatment Algorithm to BP Targets < 140/90 mm Hg Treatment Algorithm to BP Targets < 140/90 mm Hg or < 130/80 mm Hg in Patients with Diabetesor < 130/80 mm Hg in Patients with Diabetes

Dahlof et al. ASCOT-BPLA Lancet 2005;366:895-906 4

Patient Inclusion CriteriaPatient Inclusion Criteria

• Screening and baseline BP 160/100 mm Hg untreated

140/90 mm Hg following treatment with 1 or more drugs

• Age 40-79 years

• No previous MI or current clinical CHD

• 3 or more CV risk factors

Dahlof et al. ASCOT-BPLA Lancet 2005;366:895-906

5

Systolic and Diastolic Systolic and Diastolic Blood PressureBlood Pressure

mm

Hg

60

80

100

120

140

160

180

Time (years)

Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

atenolol thiazideamlodipine perindopril

137.7

136.1

79.2

77.4

Mean difference 1.9

Last visit

Mean difference 2.7

SBP

DBP

163.9

164.1

94.8

94.5

Dahlof et al. ASCOT-BPLA Lancet 2005;366:895-906 6Sever PS and Dahöf B. American College of Cardiology 2005 Scientific Sessions; March 6-9, 2005; Orlando, FL.

0.00170.65–0.910.76CV mortality

<0.00010.77–0.900.84All CV events and revascularization procedures

0.00070.66–0.900.77Fatal and nonfatal stroke

0.00480.78–0.960.86Total coronary end-point: primary end-point + new-onset angina + fatal and nonfatal heart failure

0.120.78–1.030.90Primary end-point: nonfatal MI and fatal CHD

0.0050.78–0.960.86All-cause mortality

P95% CIHazard RatioEnd Point

ASCOT BPLA: Primary and Secondary EndASCOT BPLA: Primary and Secondary End--Points for Amlodipine and Perindopril vs Points for Amlodipine and Perindopril vs

Atenolol and Atenolol and BendroflumethiazideBendroflumethiazide

2

7

Number at riskAmlodipine perindopril 9639 9475 9337 9168 8966 7863Atenolol thiazide 9618 9470 9290 9083 8858 7743

0.0 1.0 2.0 3.0 4.0 5.0Years0.0

1.0

2.0

3.0

4.0

5.0

HR = 0.90 (0.79-1.02)p = 0.1052

Atenolol thiazide(No. of events =474)

Amlodipine perindopril(No. of events = 429)

%

Primary End Point: Primary End Point: NonNon--fatal MI, fatal CHDfatal MI, fatal CHD

8

AllAll--Cause Mortality Cause Mortality

Number at riskAmlodipine perindopril 9639 9544 9441 9332 9167 8078Atenolol thiazide 9618 9532 9415 9261 9085 7975

0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

2.0

4.0

6.0

8.0

10.0

HR = 0.89 (0.81-0.99)p = 0.0247

%

Amlodipine perindopril(No. of events 738)

Atenolol thiazide(No. of events 820)

9

Summary of All End PointsSummary of All End Points

The area of the blue square is proportional to the amount of statistical information

Amlodipine perindopril better Atenolol thiazide better

0.50 0.70 1.00 1.45

PrimaryNon-fatal MI (incl silent) + fatal CHD

SecondaryNon-fatal MI (exc. Silent) +fatal CHDTotal coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure

TertiarySilent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment

Post hocPrimary end point + coronary revasc procsCV death + MI + stroke

2.00

Unadjusted Hazard ratio (95% CI)

0.90 (0.79-1.02)

0.87 (0.76-1.00)0.87 (0.79-0.96)0.84 (0.78-0.90)0.89 (0.81-0.99)0.76 (0.65-0.90)0.77 (0.66-0.89)0.84 (0.66-1.05)

1.27 (0.80-2.00)0.68 (0.51-0.92)0.98 (0.81-1.19)0.65 (0.52-0.81)1.07 (0.62-1.85)0.70 (0.63-.078)0.85 (0.75-0.97)

0.86 (0.77-0.96)0.84 (0.76-0.92)

}

10

0.60 0.70 0.80 0.90 1.00 1.50

The area of the black square is proportional to the amount of statistical information

Amlodipine perindopril better Atenolol thiazide better

DiabetesNo diabetes

Current smokerNon-current smoker

ObeseNon-obese

Older (>60 years)Younger (≤60 years)

FemaleMale

LVH according to ECG or ECHONo LVH according to ECG or ECHO

Previous vascular diseaseNo previous vascular disease

Renal dysfunctionNo renal dysfunction

With metabolic syndromeWithout metabolic syndrome

All patients

p value

0.0283<0.0001

0.00010.0030

0.0162<0.0001

<0.00010.0227

0.00150.0001

0.0056<0.0001

0.00190.0001

<0.00010.0055

0.00150.0002

<0.0001

Heterogeneity p

0.5205

0.1138

0.6753

0.7816

0.2889

0.6364

0.4863

0.7130

0.9417

Total CV events and procedures Total CV events and procedures among subgroupsamong subgroups

11

Final conclusionsFinal conclusions

• Amlodipine perindopril based therapy confers an advantage over atenolol thiazide based therapy on all major CV end points, all-cause mortality and new-onset diabetes

• Irrespective of the reasons for benefit, the standard regimen of beta-blocker thiazide should not be preferred to the amlodipine perindopril regimen for most patients

12/9/2010 2:21:13 PMStrakaJan 2008

1

ACCOMPLISH:ACCOMPLISH:Benazepril plus Amlodipine or HCT for HTN in Benazepril plus Amlodipine or HCT for HTN in

HighHigh--risk Patients risk Patients

Background: Is treatment of hypertensives with an ACE+ dihydropyridone CCBA superior to ACE + thiazide diuretic?

Methods: DB, randomized trial of 11,506 at high risk for CV events to receive either benazepril + amlidipine or benazepril + HCT. Primary endpoint was composite of death from CV causes, NFMI, NF-stroke or hospitalization for angina, resuscitation after SCA and coronaryrevascularization

Results: Terminated early after 36 months. Primary outcome occurred in552 (9.6%) of B-A group vs 679 (11.8%) in the B-HCT group (2.2% absolute risk reduction, 19.6% relative RR) (HR, 0.80, 95% CI, 0.72 to 0.90;P<0.002) AE rates consistent with clinical experiences

Conclusions: The B-A combination was superior to B-HCT in reducing CV events with hypertension for those at high risk for such events

Jamerson et al NEJM 2008;358:1547-1559

ACCOMPLISH ACCOMPLISH


Figure 1. Effects of Treatment on BP over Time.

Mean SBP and DBP were 131.6/73.3 mm Hg in the B-

A group and 132.5/74.4 mm Hg in the B–HCT

group. Mean difference in BP between groups was 0.9 mm Hg systolic and 1.1 mm

Hg diastolic (P<0.001 for both comparisons).

Systolic

DiastolicBP

ACCOMPLISH ACCOMPLISH


Figure 2. Time to First Primary Composite End Point. 552 patients with events (9.6%) in the B+A group, vs 679 patients with events (11.8%) in the B–HCT group. Relative risk reduction 20% (hazard ratio, 0.80;

95% CI, 0.72 to 0.90; P<0.001)

Ben +Aml

Ben +HCTPatients with Primary Event (%)

ACCOMPLISH


Hazard Ratios (HR) for the Primary Outcome and the Individual Components

HROutcome

B-A better B-HCT better

Straka

1

ONTARGET (NEJM 2008;358:1547-1559)Telmisartan, Ramipril, or both in patients at

high risk for vascular eventsBackground: What is role of ARBs in patients with vascular disease,

high-risk diabetes without HF vs. ACE inhibitors?

Methods: DB, randomized allocation of 8576 to 10mg ramipril, 8542 80mg telmisartan and 8502 to both. 1o composite outcome was death from CV causes, MI, stroke or hospitalization for HF

Results: Mean BP was lowered more by T and combo vs R. After 56 months, 1o outcome not different between R and T. Telmisartan had lower rates of cough (1.1 vs 4.2%; P<0.001) angioedema (0.1% vs0.3%;P<0.001) vs ramipril but higher rates of hypotensive symptoms (2.6% vs 1.7%;p<0.001). In the combo group, the 1o outcome was similar to R with an increase in hypotensive symptoms (4.8% vs1.7%;p<0.001 syncope 0.3% vs 0.2%;p=0.03) and renal dysfunction (13.5% vs 10.2%;p<0.001)

Conclusions: T equivalent to R in patients with vascular disease or high risk diabetes but with less angioedema. The combination had more AEs without increase in benefit. NEJM 2008;358:1547-1559

ONTARGETTelmisartan, Ramipril, or both in patients at high risk

for vascular events

Figure 1. Kaplan–Meier Curves for the Primary Outcome in the

Three Study Groups. The composite primary outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for

heart failure. T, R and T+R overlap

HR

NEJM 2008;358:1547-1559

ONTARGET

Figure 2. Relative Risk of the 1o Outcome and of the Main 2o Outcome. The 1o composite outcome was death from CV causes, MI, stroke, or hospitalization for

HF. The main 2o outcome was death from CV causes, MI, or stroke, same as HOPE trial.The P value is for the comparison with the noninferiority margins.

HYVET Trial (Becket et al NEJM 2008;358:1887-1898 )

Treatment of HTN in 80 + yo PatientsBackground: Does Treatment of HTN in 80+ yo patients reduce M&M?

Methods: Randomized multi country study of 80+ yo patients with sustained SBP>160mmHg to either indapamide (SR 1.5mg) vs. placebo. Perindopril (2-4mg) or PL was added if needed to achieve goal of 150/80mmHg.

Results: 1933 patients receiving Tx vs 1912 on PL well matched (mean 83.6yo, 173/90.6mmHg, 18% with Hx of CVD) followed up ~1.8 yrs

30% reduction in rate of fatal-NF stroke, (95% CI, -1 to 51;P=0.06)

39% reduction in rate of death from stroke (95% CI, 1 to 62;p=0.05),

21% reduction in rate of death from any cause (95% CI, 4 to 35;p=0.02),

23% reduction in rate of death from CV causes (95% CI, -1 to 40;p=0.06),

64% reduction in rate of HF (95% CI, 42 to 78;p<0.001), with

fewer (P=0.001) serious AEs in the treatment group vs. placebo group.

Conclusions: SR indapamide with our without perindopril in 80+year olds is beneficial.

HYVET Trial

HYVET Trial Becket et al NEJM 2008;358:1887-1898

Figure 2. Mean Blood Pressure, Measured while Patients Were Seated, in the Intention-to-Treat Population, According to Study Group

SBP

DBP

BP PLTx Group

HYVET Trial

HYVET Trial Becket et al NEJM 2008;358:1887-1898

Figure 3. Kaplan–Meier Estimates of the Rate of End Points, According to Study Group. For the active-treatment group as compared with the placebo group, the unadjusted hazard ratios (95% CIs) were as follows: for fatal or nonfatal stroke, 0.70 (0.49 to 1.01) (Panel A); for death from any cause, 0.79 (0.65 to 0.95) (Panel B); for death from cardiovascular causes, 0.77 (0.60 to 1.01) (Panel C); for death from stroke, 0.61 (0.38 to 0.99) (Panel D); and for heart failure, 0.36 (0.22 to 0.58) (Panel E).

F or NF stroke Any cause death

CV death Stroke death

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