HYPERTENSION MANAGEMENT-ANGINA

IHD

Dr. DEV PAHLAJANIDEV PAHLAJANI MD,FACC,FSCAI

HOD INTERVENTIONAL CARDIOLOGY BREACH CANDY HOSPITAL MUMBAI

May not the elevation of systemic BP be a natural response to guarantee a more normal circulation to heart, brain and kidneys (essential HTN)

-Scott RW 1946

Quoted in Prog. In Cardio.Diseases;2006;48(5);303-315

“Greatest Danger To a Man With High BP Lies In Its Discovery, Because Then Some Fool Is

Certain To Try And Reduce It”- Hay, Quoted in

Prog. In Cardio. Disease; 2006; 48(5);303-315

ANGINA MANIFESTATIONS

PRINCIPLES OF MANAGEMENT

• Reduce myocardial oxygen consumption• Reduce bp & after load• Reduce pulse rate• Reduce platelet aggregation.• Reduce contractility• Vasodilation• Improve lv function

HTN+ANGINA MANAGEMENT GOALS

• Relief of symptoms• CONTROL HTN TARGET LEVELS TOReduce LV massReduce deathImprove endothelial function, reduce

death, MI,HF,REVASC,CVD,CKD

Hemodynamic and Electrophysiologic Changes of CCBs done

Hemodynamic and Electrophysiologic effects of Calcium antagonists

Nifedipine (a) Diltiazem Verapamil

Coronary dilation ++ ++ +Peripheral dilation ++++ ++ +++Negative inotropic + ++ +++AV conduction +++ ++++Heart rate

Blood pressure ++++ ++ +++Sinus node depression

++ ++

Cardiac output ++a- or other dihydropyridines+, minimal effect; ++++, maximal effect; , no significant change; ,decrease; , increase

Calcium channel blockers• Dihydropyridine CCBs are widely used to treat hypertension and ischemic

heart disease

• They inhibit L-type calcium channels found in vascular smooth muscle, dilating the arterioles

• Meta-analysis of several trials involving newer CCBs (amlodipine, felodipine, isradipine, nicardipine, or nisoldipine) found higher risk of mortality compared to other antihypertensive drugs

• Nifedipine – Extensively evaluated drug– Favorable effects on CV mortality or morbidity with long-lasting

formulations

Reversal of Endothelial DysfunctionA Promising New Approach to Reduce Vascular Complications

STATINS

CALCIUM ANTAGONISTSACE-INHIBITORS

BETA BLOCKER

(Maximum clinical evidencewith Long-acting Nifedipine)

(Clinical evidence with Nebivolol)

Reversal ofEndothelial Dysfunction

ATHEROPROTECTIONREVERSAL OF VASCULAR REMODELING

ARB

Nifedipine XL - Reversal of Endothelial DysfunctionENCORE - I Trial

(Effect of Nifedipine and Cerivastatin on recovery of Coronary Endothelial function)

Study Design:

• Randomized, Placebo-controlled, Double Blind Multi-centric Clinical Trial Carried Out

Across Europe, Israel and Australia

• 800 Coronary Artery Disease Patients (Selected for Angioplasty) Randomized to 4 Groups

(n=200/Group)

* Placebo * Nifedipine XL (30-60mg/d)

* Cerivastatin * Nifedipine XL + Cerivastatin

• Coronary Endothelial Function Assessed at The Beginning and

at the End of 6 Months Treatment Using Acetylcholine Testing

• Blood Flow Velocity and Coronary Diameter Was Measured Using Flowmapping and

Quantitative Angiography Techniques

The ENCORE Investigators .Circulation. 2003;107:422

Nifedipine XL - Reversal of Endothelial DysfunctionENCORE - I Trial

(Effect of Nifedipine and Cerivastatin on recovery of Coronary Endothelial function)

Study Results:

*Treatment With Nifedipine XL (Alone) Was Associated With Significant 90% Improvement in Coronary Endothelial Function as Compared to Placebo

The ENCORE Investigators .Circulation. 2003;107:422

Nifedipine and athero-protection coronary calcification study

Hypertension, 2001, 37(6), 1410-1413

Aim: To detect the changes in calcium deposition score in coronary arteries of patients

using sophisticated double-helix CT scanning (Calcium deposition score is an index of atherosclerosis and is directly proportional

to the burden of atherosclerosis)Findings:

nifedipine XL was associated with significantly slower progression of coronary calcification in 3 years as compared with diuretic treatment, despite equivalent B.P.

reduction in both arms

Nifedipine and athero-protectionAmerican J. Cardiology, 1989.

113 patients ISDN with recent onset, stable angina, followed up for 2 years, Nifedipine v/s Propranolol v/s Progression, Steadiness and Regression of Coronary Disease

* The number of stenoses with evidence of progression was significantly smaller after nifedipine.

NifedipineN=39

PropranololN= 36

ISDNN=38

No. of patients with progression

12 (31%) * 19(53%) 18(47%)

No. of patients with steadiness

20(51%) 14 (39%) 17 (45%)

No. of patients with regression

7(18%) 3(8%) 3(8%)

Antihypertensive Efficacy Mean Blood Pressure

Nifedipine GITSDiuretic Combination

138 mmHg

82 mmHg

180

160

140

120

100

80

60

0 2 4 8 12 18 36 70 87 121 138 173 190 225 242

mm

Hg

Year 1

Year 2

Year 3

Year 4

Week

Systolic

Diastolic

176 mmHg

99 mmHg

Angina Pectoris, Transient Ischemic Attacks (TIAs), Renal Failure

Individual Secondary Endpoints (Non-fatal)

0

0.5

1.0

1.5

2.0

2.5

% o

f Pati

ents

0.3 0.4

Angina pectoris TIAs Renal Failure*p = 1.0 p = 0.38

Nifedipine GITSDiuretic Combination

3.0

1.8

0.8 0.8

2.4

*Decrease in estimated GFR > 25% compared to value at inclusion at 2 repeated measures

0

0.5

p = 0.10

CASE BASED HYPERTENSION MANAGEMENT (CASE 1)

• 65 yrs.Male• H/o anterior wall MI 6yrs.Back• Had post MI angina• CABGS 5yrs. back• SOB Class 2• BP 176/76,LVEF 35%• NON DM,CREAT.1.4

Effect of ACE-I in post MI patients with HF or LV dysfunction

Mortality• SAVE: 25% (placebo) vs 20% (captopril) - 19% RRR• AIRE: 23% (placebo) vs 17% (ramipril) - 27% RRR

• TRACE: 42.3% (placebo) vs 34.7% (trandolapril)- 24% RRR

Study Patient population Randomized to Results

ACE-I-Intolerant

CHARM-Alternative NYHA II-IVACE-I intolerant patients

Candesartan vs. placebo 23% RRR in primary endpoint (CV death + CHF hospitalize)

On ACE-I,PLUS ARB

CHARM-Added NYHA II-IV Candesartan vs. placebo 15% RRR in primary endpoint (CV death + CHF hospitalize)

Val-Heft NYHA II-IV Valsartan vs. placebo No mortality difference (but 13% RRR in mortality + morbid)

ACE-I vs. ARB

ELITE I NYHA II-IV Losartan vs. captopril 46% risk reduction in all cause mortality with losartan (secondary outcome)

ELITE II NYHA II-IV Losartan vs. captopril No mortality differenceNo difference in CHF admissions

OPTIMAAL Post MI LV dysfunction Losartan vs. captopril Trend towards better outcomes all cause mortality (p= 0.7), SCD (p=0.7), in captopril group

VALIANT Post MI LV dysfunction Valsartan vs. captopril No difference in all cause mortality or CV morbidity and mortality

ARB Trials

Eichhorn EJ, JCF. 2000;6(suppl 1):40-46.

LVEF

Time (months)

Biologic Effect

Pharmacologic Effect

b-Blocker Initiated

b-Blocker Discontinued

00 11 33 66 88

-Blocker Effects On Ejection Fraction in Heart Failure

Mortality by Baseline Plasma Norepinephrine Level (PNE)

Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48.

100

80

60

40

20

0 6 12 18 24 30 36 42 48 54 60

Months

Cum

ulati

ve M

orta

lity

(%)

PNE > 900 pg/mL

PNE > 600 and < 900 pg/mLPNE < 600 pg/mL

2 YearP < .0001

OverallP < .00010

MERIT HF – ALL-CAUSE MORTALITY

Carvedilol Or Metoprolol European Trial COMET

17%

Lancet 2003; 362: 7-13

Per cent of patients able to tolerate carvedilol treatment, grouped according to traditional contraindications and

precautions in prescribing a -blocker

88 85 86 84

12 15 14 16

020406080

100

All p

atien

ts(n

=795

)

COPD

/ast

hma

(n=8

9)

Dia

bete

s(n

=127

)

PVD

(n=5

8)

Tolerated Not Tolerated

Per c

ent

Heart 2000; 84:615-619

EPHESUS

• 6642 patients:a) 3-14 days post MI, b) EF<40, c) CHF (rales, pulmonary venous congestion seen

on CXR, 3rd heart sound) OR Diabetes• randomized to 25 mg eplerenone titrated up

to 50 mg po qd

NEJM 2003;348:1309-21

EPHESUS

• Results:– One year mortality: 15% risk reduction (11.8% vs 13.6%)– CV death or cardiovascular hospitalizations (26% vs 30.0%)

• (75% of patients on beta blockers)

• adverse effects: – serious hyperkalemia (K>6) Epler- 5.5% vs plac- 3.9% (p=.002)– serious hypokalemia (K<3.5) Epler- 8.4% plac- 13.1% (p<.001)– gynecomastia- 0.5% vs 0.6%

COPERNICUS : SURVIVAL

Copernicus : major outcomes

Carvedilol(n = 1156)

placebo (n=1133)

RR

All-cause mortality

11 % 17 % 35 %

Hosp. + Mortality

37 % 45 % 24 %

CARVEDILOL – EFFECT ON MAJOR CLINICAL EVENTS

• Results: • 46% mortality placebo vs

35% spironolactone (30% RRR)

• adverse effects: – 10% of pts in

spironolactone group developed gynecomastia.

– -serious hyperkalemia (K>6) 14% vs 10% (not statist sig)

RALES

Spironolactone-induced reduction in systolic (dark blue cones) and diastolic blood pressure (red cones) at 6 weeks,

3months, and 6months of follow-up in subjects with resistant hypertension done

CASE 2

• Male 54 yrs obese built increased ABD girth

• Angina on effort class ii

• HTN BP 206/92,pulse 92/min

• Coronary ANGIO OM CX 70%.PD 70% EF 55%

• Advanced medical treatment and SOS PTCA with

stents

BETA BLOCKERS IN ANGINA

• Reduce myocardial oxygen consumption• Reduce heart rate• Reduce BP• Reduce double product• Reduce CAT.• Antiplatelet Effect

CALCIUM BLOCKERS

• Decrease BP

• Vasodilatation

• Nefedipine felodipine and amlodipine cause

tachycardia

Mortality benefits for ACEI trials

AMI AMI with LVD CHF

TRIALACEI

Dose†

ISIS IVcapto50x2

GISSI 3lisino

10

SAVEcapto50x2

AIRErami5x2

TRACEtrandola

4

CONSENSUSenala

40

SOLVDenala

20

.84.74-.95

.73.56-.95

.78.67-.91

.73.60-.89

.81.68-.97

.88*.79-.99

.93*.87-.99

RR 5

%CI

*odds ratio †maximum daily dose

0

0.1

0.2

0.3

0.4

0 1 2 3 4 5

number at riskACE inhibitors 2995 2250 1617 892 223Placebo 2971 2184 1521 853 138

time since randomization (years)

cum

ulat

ive

mor

talit

y (%

)

placebo

Meta-analysis of AIRE, TRACE, SAVE

Flather MD, et al. Lancet 2000; 355(9215):1575 - 81

26% reductionp < 0.0001

ACE Inhibitors

CV Disease Risk Doubles withEach 20/10 mm Hg BP Increment*

*Individuals aged 40-70 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure

CVdisease

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

Lewington S, Cardiovascular Issues in Ageing Pilots. et al. Lancet. 2002; 60:1903-1913

38

Diseases Attributable to Hypertension

Adapted from: Arch Intern Med 1996; 156:1926-1935.

AllVascular

JNC VII Classification

CategoryCategory SBP (mm Hg)SBP (mm Hg) DBP (mm Hg)DBP (mm Hg)

Normal < 120 < 80

Pre – hypertension 120-139 80-90

Hypertension

Stage 1 140 – 159 90 – 99

Stage 2 160 and above 100 and above

AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; ββB, B, ßß--blocker; CCB, calcium channel blocker; MI, myocardial infarction; blocker; CCB, calcium channel blocker; MI, myocardial infarction; CAD, coronary artery disease. Chobanian AV, et al. CAD, coronary artery disease. Chobanian AV, et al. JAMA.JAMA. 2003;289(19):2560-2572. 2003;289(19):2560-2572.

The Seventh Report of the Joint National Committee

Compelling Compelling IndicationsIndications DiureticDiuretic ßBßB ACEIACEI ARB CCBCCB AAAA

Heart failureHeart failure

Post-MIPost-MI

High CAD riskHigh CAD risk

DiabetesDiabetes Chronic kidneyChronic kidney

diseasedisease

Recurrent strokeRecurrent strokepreventionprevention

JNC 7: Algorithm for Treatment of Hypertension

Prehypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg)

Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease)

Without Compelling Indications With Compelling Indications

Prehypertension

Stage 1 Hypertension (SBP 140-159 or DBP 90-99 mm Hg)

Thiazide-type diuretics for most; may consider ACEI, ARB, BB, CCB, or combination.

Stage 2 Hypertension (SBP 160 or DBP 100 mm Hg)

2-drug combinations for most(usually thiazide-type diuretics andACEI, or ARB, or BB, or CCB).

Drug(s) for compelling indications

Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB)as needed.

LIFESTYLE MODIFICATIONS

If not at goal BP, optimize dosages or add additional drugs until goal BP is achieved. Consider consultation with hypertension specialist.

INITIAL DRUG CHOICES

HF of Ischemic EtiologyHF of Ischemic EtiologyHF of Ischemic EtiologyHF of Ischemic Etiology

ACS - STEMIACS - STEMIACS - STEMIACS - STEMIACS – UA and NSTEMIACS – UA and NSTEMIACS – UA and NSTEMIACS – UA and NSTEMICAD and Stable AnginaCAD and Stable AnginaCAD and Stable AnginaCAD and Stable Angina

Primary PreventionPrimary PreventionPrimary PreventionPrimary Prevention

Diagnosis

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

ASC: acute coronary syndrome, UA: Unstable angina, NSTEMI: Non-ST segment elevation myocardial infarction, STEMI: ST segment elevation myocardial infarction, HF: Heart failure

<130/80, but consider <120/70<130/80, but consider <120/70<130/80, but consider <120/70<130/80, but consider <120/70

<130/80<130/80<130/80<130/80

<130/80 <130/80 Diabetes, Chronic Kidney Disease, CAD, CAD Diabetes, Chronic Kidney Disease, CAD, CAD Equivalents, or Framingham Risk Score Equivalents, or Framingham Risk Score ≥10%≥10%

<130/80 <130/80 Diabetes, Chronic Kidney Disease, CAD, CAD Diabetes, Chronic Kidney Disease, CAD, CAD Equivalents, or Framingham Risk Score Equivalents, or Framingham Risk Score ≥10%≥10%

Target BP (mm Hg)

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

AHA Scientific Statement—Treatment of Hypertension in the Prevention and Management of

Ischemic Heart Disease

Phase of Phase of TreatmentTreatment

Acute Acute treatmenttreatment

SecondarySecondarypreventionprevention

OverallOverall

Total #Total #PatientsPatients

28,97028,970

24,29824,298

53,26853,268

0.50.5 1.01.0 2.02.0RR of deathRR of death

b-blocker betterb-blocker better

RR (95% CI)RR (95% CI)

Placebo betterPlacebo better

0.87 (0.77-0.98)0.87 (0.77-0.98)

0.77 (0.70-0.84)0.77 (0.70-0.84)

0.81 (0.75-0.87)0.81 (0.75-0.87)

blocker Evidence: Secondary Prevention

Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.Philadelphia, PA: W.B. Sanders, 2001, 1168.

Summary of Secondary Prevention Trials of b-blocker TherapySummary of Secondary Prevention Trials of b-blocker Therapy

CI=Confidence interval, RR=Relative riskCI=Confidence interval, RR=Relative risk

––22%22% ––20%20% ––20%20%

Hanes DS et al. Hanes DS et al. J Clin Hypertens (Greenwich).J Clin Hypertens (Greenwich). 2001;3(4):236-243. 2001;3(4):236-243.

Risk Reduction With β-Blockersin Post-MI Patients

––30%30%

––40%40%

––20%20%

––10%10%

0%0%

––33%33%

OverallOverallmortalitymortality

SuddenSuddencardiaccardiacdeathdeath

Non-suddenNon-suddendeathdeath Nonfatal MINonfatal MI

15 Trials (n =18,995)15 Trials (n =18,995)

COMET

DRUGS :

CARVEDILOL 3.125 MG BID TARGET DOSE 25 MG BID

METOPROLOL5 MG BIDTARGET DOSE 50 MG BID

ACE-I & DIURETICS USED CONCURRENTLY

COMET TRIAL

Carvedilol Or Metoprolol European Trial COMET

Lancet 2003; 362: 7-13

• 2647 patient

• Ischaemic or non ischaemic

• Moderate to severe HF (class III NYHA)

• Bisoprolol upto 10 mg day or placebo

• Conventional therapy

• Upto 28 months (average 16 months)

Cardiac insufficiency bisoprolol studyCIBIS-II

Lancet 1999 353; 913

SURVIVAL CURVE – CIBIS II

~ 30 % reduction of all-cause mortality

BESTß-BLOCKER EVALUATION SURVIVAL TRIAL

• N = 2708 patients• Survival in patients with moderate to severe heart

failure– NYHA III – IV– EF < 35 %

BEST : MAJOR OUTCOMESBucindolol (n=1263)

Placebo (n=1260) Risk reduction

All cause mortality 30.2 % (Annualised rate 14.9%)

33.0% (Annualised rate 16.6.%)

8.5% (NS)

Cardiovascular mortality*

24.4% 27.9% 12.5% (p= 0.04)

All hospitalisation 61% 64% 4.7% (NS)

Heart failure hospitalisation

35% 42% 16.7% (p=0.001)

Progression to death/ transplant

31.6% 35% 10% (NS)

* No significant difference in death due to heart failure, sudden death, pump failure or myocardial infarction

EFFECT OF ß-BLOCKADE BY AETIOLOGY AND NYHA CLASS

PHARMACOLOGIC DIFFERENCESß1 Blockade ß2

Blockade1 Blockade

ISA Ancillary effects *

Carvedilol -

Metoprolol - - - -

Bisoprolol - - - -

Bucindolol - -

* Anti- oxidant, anti-endothelin, anti-proliferative

CARVEDILOL – EFFECT ON MAJOR CLINICAL EVENTS

EVENT-FREE SURVIVAL IN THE TWO GROUPS WITH (THICK LINE) AND WITHOUT (THIN LINE) ECHOCARDIOGRAPHIC LVH AT THE

BASELINE BSA INDICATES BODY SURFACE AREA

Prob

abili

ty o

f Eve

nt F

ree

Surv

ival

100

90

80

70

60

4

3

2

1

0

Rate

of E

vent

s (p

er 1

00 p

atien

t-ye

ars

Baseline LV mass > 125 g/BSABaseline LV mass < 125 g/BSA

p = 0.013

0 100 200 300 400 500 < 125 > 125Time to Event, week Baseline LV mass, g/BSA

EVENT RATE IN SUBSET WITH ECHOCARDIOGRPHIC LVH ATE BASELINE VISIT

0 100 200 300 400 500 Regressors Non RegressorsTime to Event, week

Prob

abili

ty o

f Eve

nt F

ree

Surv

ival

%

7

6

5

4

3

2

1

0

Rate

of E

vent

s (p

er 1

00 p

atien

t-ye

ars

100

90

80

70

60

50

40

Regressors (N=52)

Non regressors (N=60)

p = 0.002

Circ. 1998, 97, 48

Baseline LV mass > 125 g/BSAFollow-up mass < 125 g/BSABaseline LV mass > 125 g/BSAFollow-up mass > 125 g/BSA

SOME DRUGS THAT MAY CAUSE ERECTILE DYSFUNCTION

Group Group

Antihypertensive Diuretics

Vasodilators e.g. hydralazine

Central sympatholytics, e.g. methyldopa, clonidine, reserpine

Ganglion blockers e.g. guanethidine

Beta-Blockers

Calcium antagonists

ACE inhibitors

Lipid-modifying agents Clofibrate

Antimicrobials Ethionamide, Vidarabine

Cardiac-active agents Digoxin

Gastrointestinal agents Cimetidine

43210-1-2-3-4

43210-1-2-3-4

43210-1-2-3-4

43210-1-2-3-4

mm Hg

mm Hg

Sildenafil(n=965)

Placebo(n=503)

Sildenafil(n=386)

Placebo(n=244)

Change in SBP

Change in DBP

Change in SBP

Change in DBP

Blood pressure changes in patients not on antihypertensive therapy (top) and in those receiving 1 of 5 classes of antihypertensive drugs (bottom) during concurrent treatment With sildenafil or

placebo. DBP = diastolic blood pressure; SBP = systolic blood pressure. Data on file, Pfizer Inc.

B) Antihypertensive drugs

A) No Antihypertensive

ADRENAL HYPERP.JSP

DOPPLER

CT ANGIO

Cilnidipine – Heart Rate

• Study conducted in 2920 hypertensive patients:

– Treatment with cilnidipine and ARBs showed

significant reductions in heart rate

• 24-h ambulatory blood pressure monitoring study with

hypertensive patients

– Reductions in heart rate significantly greater in the

cilnidipine group than the amlodipine group

Nagahama S, et al. Hypertens Res 2007;30:815–822

Effects of cilnidipine on norepinephrine (NE) secretion

Cilnidipine attenuates norepinephrine release from sympathetic nerve endings

Takahara A. Cardiovascular Therapeutics 2009; 27; 124–139

Cilnidipine Summary of Effects• Inhibits sympathetic N-type Ca2+ channels and vascular L-type Ca2+ channels

• Does not suppress cardiac functions at vasodilator doses

– Shows antisympathetic profiles

– Comparable BP reduction

• Better reduction of heart rate

• More vascular effect than cardio effect

• Favorable effect on glucose homeostasis

• Improves glomerular filtration, renal protection

• Reduces proteinuria

THANK YOU!!