Newer Antihypertensive Drugs

BushraAbdul Hadi Philadelphia University

Peripheral vascular disease

Morbidity

Disability

Renal disease

CADCHFLVHStroke

Hypertension

National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.

Hypertension: A Significant CV and Renal Disease Risk Factor

“Older generation drugs used to bring down the B.P. fairly well at reasonable cost.”

Then, Why do we need new drugs ?• Observational and limited controlled trials

then showed marginal benefits of BP lowering for CVAs and IHD

• Unfriendly dosing schedule• Unpleasant side effects

Vasculopathy continuum

Risk Factors Endothelial Dysfunction

CAD CHF CVA PAD

CKD HTN Metabolic syndrome

Hypertension

Na+ Handling Sympathetic N system RAAS

Genetics Environment Psycho-social

HTN : Old and New

• Diuretics • Reserpine• Guanethidine• Alpha Methyl Dopa

ACE InhibitorsAngiotensin Receptor BlockersBeta BlockersCentral Alpha Agon.Calcium Channel BlockersDiureticsDirect VasodilatorsAldosterone Anta.NEP Blockers

Heart

– Myocardial hypertrophy

– Interstitial fibrosis

Coronary Arteries

– Endothelial dysfunction with decreased release of nitric oxide

– Coronary constriction via release of norepinephrine

– Formation of oxygen-derived free radicals via NADH

(nicotinamide adenine dinucleotide) oxidase

– Promotion of inflammatory response and plaque instability

– Promotion of low-density lipoprotein cholesterol uptake

Adapted from Opie and Gersh. Drugs for the Heart, 2001.

Potential Pathogenic Propertiesof Angiotensin II

Kidneys

– Increased intraglomerular pressure– Increased protein leak– Glomerular growth and fibrosis– Increased sodium reabsorption– Decreased renal blood flow

Adrenal Glands

– Increased formation of aldosterone Coagulation System

– Increased fibrinogen– Increased PAI-1 (plasminogen activator inhibitor-1) relative to

tissue plasminogen factor

Adapted from Opie and Gersh. Drugs for the Heart, 2001.

Potential Pathogenic Propertiesof Angiotensin II (continued)

Aldosterone

Sympathetic activation

Growthfactor stimulation

NA+ retentionH2O retentionK+ excretionMg+ excretion

Vascular smooth muscle constriction

Angiotensinconvertingenzyme(ACE)

Angiotensin II

Liver secretes angiotensinogen

Kidneys secreterenin

The Renin-Angiotensin-Aldosterone (RAA) System

Angiotensinogen Angiotensin I

Adrenal cortex secretes aldosterone

Blood Renin

RAA System Pathways to Target Receptor Sites

AldosteroneAngiotensinogen

Angiotensin I Angiotensin IICE

Renin

Chymase

Bradykinin Inactive

K+Na+

ACTHOtherAdrenal

Vascular

Myocardial

Renal

CNS

LosartanAtenolol

(n=4,605) (n=4,588) RR (%) p-value

Primary composite† 508 588 -13 .021

CV mortality 204 234 -11 .21

Stroke 232 309 -25 .001

MI 198 188 +7 .49

Total mortality 383 431 -10 .13

New onset DM‡ 241 319 -25 <.001

LIFE: Primary and Select Secondary Outcomes

Adjusted*

* For degree of LVH and Framingham risk score at randomization† Number of patients with a first primary event‡ In patients without diabetes at randomization (losartan, n=4,019; atenolol, n=3,979)Adapted from B Dahlöf et al. Lancet. 2002;359:995-1003.

-22(P<.001)

MI, Stroke,CV Death(primary

end point)

-26(P<.001)

CV Death

-20(P<.001)

MI

-32(P<.001)

Stroke

-16(P=.005)

All-causeDeath

-35

-30

-25

-20

-15

-10

-5

0

Ris

k R

educ

tion

(%)

HOPE: Risk Reduction of CV EventsAssociated with ACEI (RAS Inhibition)

Treatment

Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.

Mechanism of Action ofMechanism of Action ofAngiotensin II Receptor AntagonistsAngiotensin II Receptor Antagonists

Angiotensinogen

Angiotensin I

Angiotensin II

AT2 receptor

AT1 receptor Other ATreceptors

Bradykinin

Inactive

peptides

VasodilationAttenuate growth anddisease progression

ACEinhibitors

Alternatepathways

AIIRAs

?

?

Val-HeFT

Results

• Overall mortality was similar in the two groups

• 13% RRR (p=.009) in combined end point

• Predominantly because of a 27% decrease in hospitalization for HF in the valsartan group

• Subgroup analyses:– Valsartan had a favorable effect in patients receiving neither an

ACE inhibitor nor a beta-blocker– Valsartan had a favorable effect in patients receiving an ACE

inhibitor or a beta blocker– Valsartan demonstrated a statistically non-significant trend

towards an adverse outcome in patients receiving an ACE inhibitor and a beta blocker

ADA Guidelines on Management of Diabetic Nephropathy

Hypertensive Type 2 Diabetic Patients*

ARBs are the initial agents of choiceType 1 Diabetics with or without

hypertension*

ACEIs are the initial agents of choice If one class is not tolerated the other

should be substituted* With microalbuminuria and clinical proteinuria. Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.

Effect of ACE Inhibition on Nephropathy in Type 1

Diabetes

* P=.006 vs placebo.* P=.006 vs placebo. Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.

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CaptoprilCaptopril

PlaceboPlacebo

Follow-up (y)Follow-up (y)

00 11 22 33 4400

1010

2020

3030

4040

**

ACE Inhibitors and ARBs

• Captopril• Enanlapril• Lisinopril• Ramipril• Perindopril• Quinapril

LosartanIrbesartanCandesartanValsartanTelmisartanOlmesartan

Aliskiren

Proven role of Beta Blockers in Various Indications

- Hypertension

- Diabetes Mellitus

- CHF

- CAD

Kje

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Effect of Beta-Blockers onmortality following myocardial infarction

Effect of Beta-Blockers onmortality following myocardial infarction

Diabetes mellitus, all

Diabetes mellitus,beta-blocker

No diabetes mellitus,no beta-blockerNo diabetes mellitus,beta-blocker

1 ye

ar-m

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(%)

17

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10

23

13

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5

10

15

20

25

10

Diabetes mellitus,no beta-blocker

No diabetes mellitus, all

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Usefulness of beta-blocker therapy in patients With Diabetes Mellitus and CAD (BIP)

Usefulness of beta-blocker therapy in patients With Diabetes Mellitus and CAD (BIP)

Year

Without ß-blockers

With

ß-blockers

P= 0.0001

1 2 3 4 50.75

0.80

0.85

0.90

0.95

1.00

Su

rviv

al r

ate

Effect of Beta-Blockers on Mortality in Heart Failure Patients

34% lower risk (0.53–0.81)P=0.0062 after adjusted interim analysis

MERIT-HF (metoprolol)

34% lower riskP< 0.0001

CIBIS-II (bisoprolol)

38% lower risk (18%-53%)P< 0.001

US Carvedilol

35% lower risk*COPERNICUS (carvedilol)

8.5% lower riskP=NS

BEST (bucindolol)

Clinical Trial

All-cause mortality

All-cause mortality

Combined end point: risk of hospitalization or death

All-cause mortality

All-cause mortality

Trial End Point Risk Reduction, % (95% CI)

*Preliminary data from XXII Congress of the European Society of Cardiology

Effects of Metoprolol CR and Placebo on Neurohormonal Activation

250

225

200

175

150

125

100

75

50

25

0

250

225

200

175

150

125

100

75

50

25

0

165182

35.9 38.9

105

128

*147

99

30.9

113129

*34.3

Placebo Metoprolol

NS

Plasmarenin ng/ml

Angiotensin II pg/ml

Aldosterone pg/ml

Plasmarenin ng/ml

Angiotensin II pg/ml

Aldosterone pg/ml

Baseline

24 weeks

Baseline

24 weeks

*P<0.05NS: Non Significant

The Resolvd Investigators. 1999.

Mega-trials on: metoprolol, bisoprolol, carvedilol & bucindolol.

Consistent good results in mild / moderate HF.

Significant ↓ in rate of hospitalisation.

Fair improvements in symptoms & QOL.

Improvements in hemodynamics of HF & remodeling.

Results in severe HF are not uniform.

Bucindolol in BEST showed no benefits.

Sub-analysis of CIBIS-II (Bisoprolol) & MERIT-HF: ↓ benefits in more severe HF.

COPERNICUS: significant benefits in severe HF.

Effect of -Blocker in Heart Failure

Lipophilic beta blockers are an ideal choice in patients at

high risk of SCD, prior MI, HT,CHF

Beta Blockers

• Propranolol• Atenolol• Metoprolol( Sustained Release)• Bisoprolol• Carvedilol

DiureticsALLHAT

Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.

HydrochlorthiazideMetolazoneFurosemideTorsemideAmiloride

Calcium Channel Blockers

Very effective in lowering BP Safe OD or BID Dose No significant outcome benefits Peripheral edema

Nifedipine(Long Acting)AmlodepineVerapamilNicardepineLercanidipineFelodepine

Miscellaneous• Direct Vasodilators

– Dihydrallazine– Minoxidil– Prazosin

• Central Alpha Agonists– Clonidine– Moxolidine

• Aldosterone antagonists– Spironolactone– Eplerenone

• Indapamide

Benefits of Lowering BP

Average Percent Reduction

Stroke incidence 35–40%

Myocardial infarction 20–25%

Heart failure 50%

U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

National Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program

National Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program

Blood Pressure Classification

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 Hypertension

140–159 or 90–99

Stage 2 Hypertension

>160 or >100

BP Classification SBP mmHg DBP mmHg

Compelling Indications for

Individual Drug ClassesCompelling Indication

Initial Therapy Clinical Trial BasisACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES

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

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

THIAZ, BB, ACEI, ARB, ALDO ANT

BB, ACEI, ALDO ANT

THIAZ, BB, ACE, CCB

Heart failure

Postmyocardialinfarction

High CAD risk

Diabetes

Chronic kidney disease

Recurrent stroke prevention

Compelling Indications for Individual Drug Classes

Compelling Indication

Initial Therapy Options

Clinical Trial BasisNKF-ADA Guideline, UKPDS, ALLHAT

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

PROGRESS

THIAZ, BB, ACE, ARB,

CCB

ACEI, ARB

THIAZ, ACEI

Cardiovascular Diseases

• Cerebrovascular disease– Indication for treatment, except immediately

after ischemic cerebral infarction.

• Coronary artery disease–Benefits of therapy well established.

• Left ventricular hypertrophy–Antihypertensive agents (except direct

vasodilators) indicated.–Reduced weight and decreased sodium

intake beneficial.

Cardiovascular Diseases (continued)

• Cardiac failure–ACE inhibitors, especially with digoxin or

diuretics, shown to prevent subsequent heart failure.

• Peripheral arterial disease–Limited or no data available.

For persons over age 50, SBP is a more important than DBP as CVD risk factor

Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.

Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.

Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD.

New Features and Key Messages

JNC-VII New Features and Key Messages (Continued)

Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes.

Certain high-risk conditions are compelling indications for other drug classes.

Most patients will require two or more antihypertensive drugs to achieve goal BP.

If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

Preventable CHD Events from Control of Hypertension in US Adults

(Wong et al., Am Heart J 2003; 145: 888-95) (cont.)

• The greatest impact (absolute numbers) from control of hypertension occurs in men, older persons, and those with isolated systolic hypertension

• The greatest proportion of preventable CHD events from control of hypertension occurs in women

• Optimal control of blood pressure could prevent more than one third of CHD events in men and more than half of CHD events in women

Evolution of Antihypertensive Therapies

Directvasodilators

-blockers VPIs

OthersPeripheral

sympatholytics

Ganglion blockers

Veratrumalkaloids

Central 2 agonists

Calciumantagonists-

non DHPs

-blockers

Thiazidesdiuretics

Calciumantagonists-

DHPs

ARBs

1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2001

ACEinhibitors

Effectiveness

Tolerability

We are still evolving towards finding an Ideal Antihypertensive

Preventable CHD Events from Control of Hypertension in US

Adults(Wong et al., Am Heart J 2003; 145: 888-95)

19

37

31

56

21

11

39

21

0

10

20

30

40

50

60

PA

R%

/ N

NT

Men PAR% Women PAR% Men NNT Women NNT

Treatment to <140/90 mmHg Treatment to <120/80 mmHg

PAR% = population attributable risk (proportion of CHD events preventable), NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%

Compelling Indications for Certain Drug Classes

HTN with CAD Beta blockers: cardioprotective

(reinfarction, arrhythmias and sudden death)

ACE inhibitors: MI with systolic dysfunction- heart failure and mortality improved

Aliskiren is a novel, completely nonpeptide, orally active renin inhibitor that blocks the first and rate-limiting step of the renin-angiotensin system

Alagebrium, an advanced glycation end product (AGE) crosslink breaker, has been shown to reduce SBP in patients with uncontrolled systolic hypertension,

progestin drospirenone and 17beta-estradiol (DRSP/E2), developed for postmenopausal hormone replacement therapy, has been shown to lower both clinic and ambulatory SBP in postmenopausal women

Adapted from: Eichhorn EJ, Bristow MR. Circulation. 1996;94:2285-2296.

Pathophysiology of Heart Failure

Cell death

Altered gene expression

Growth and remodeling

Ischemia and energy depletion

Activation of RAA System, SNS, and cytokines

Increased load

Cardiac injury

Direct toxicity

Apoptosis Necrosis

Reduced systemic perfusion

Pathogenesis of HT

Reasons are

mulitfactorial..

Renin

Angiotensin II Angiotensin I

Increased Na+ & water reabsorption

Vasoconstriction

Summary