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Hypertension in Clinical Practice Case Study

Dr. Tarek El Zawawy gy, Alex. University y Professor of Cardiology, CardioAlex Conference 2010

Case Study
Mr. SB is a 40 y year old male, smoker, active, with no
significant past medical history & on no medication, with confirmed elevation in BP on repeated visits.

Headache Visual Vi l di disturbances. t b

Family History:
Father With 20 years of Hypertension & IHD Hypertensive Brother at the age of 51.

Past P t History: Hi t
Treatment for mental depression for 3 years

Case Study (Cont (Cont.) )

Physical Examination:
Height: 178 cm Weight: 96 kg BP: 150/90 Heart rate: 76 Chest: Clear to P&A Heart: Regular rhythm, 0 gallops or murmurs audible Abdomen: soft, 0 bruits or organomegaly

ECG: voltage g criteria for LVH Chest X-Ray: Normal heart size, 0 Lung Pathology Urine alysis: Normal

Case Study (Cont (Cont.) )

Laboratory Findings:
Na 140, K 3.9, 39 Cl 102, FBS 115, OGTT 160 BUN 15, Creatinine 1.1, Cholesterol 270 (LDL 210, HDL 45),] Triglycerides 250, Hct 42

Q1: What is the initial diagnosis of Mrs. Mrs SB?

Grade I Hypertension, Obese, IGT & Dyslipidemia

Grade II Hypertension, Obese & Diabetic

Grade G d I Hypertension, H i Obese Ob & Dyslipidemia D li id i

Grade II Hypertension, Obese, Diabetic & Dyslipidemia

JNC VII Classification

Category Normal Pre hypertension Hypertension Stage 1 Stage 2

SBP (mm Hg) < 120 120-139

DBP (mm Hg) < 80 80-90

140 159 160 and above

90 99 100 and above

Risk Stratification according to ESC/ESH

Q2: How do you classify this patient according to ESC-ESH risk stratification?
Low added risk

Moderate added risk

High Hi h added dd d risk i k

Very high added risk

Risk Stratification according to ESC/ESH

Q3: According to Guidelines, This patient should be treated by ...

Pharmacological treatment only

Lifestyle modification only

Pharmacological Ph l i l treatment & Lif Lifestyle l modification difi i

Just Stop Smoking

Initiation of antihypertensive treatment(ESC2007)

What is the Goal of BP in this patient ?

12 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

AHA Perspective/Hypertension Management and BP Goals Summary of Main Recommendations

Area of concern General CAD prevention

BP Target (mm Hg) <140/90

Lifestyle modification Yes

Specific Drug Indications Any effective antihypertensive drug or combination bi ti ACEI or ARB or CCB or thiazide or combination

High CAD risk*




<130/80 <130/80 <130/80 <120/80

Yes Yes Yes Yes

-blocker and ACEI or ARB -blocker and ACEI or ARB -blocker and ACEI or ARB ACEI or ARB and -blocker and aldo antagonist and thiazide or loop diuretic and hydral/nitrate (blacks)

* diabetes, CKD, CAD or equivalent weight loss if appropriate, healthy diet, exercise, smoking cessation and alcohol moderation evidence supports ACEI or ARB, CCB, or thiazide as first-line if anterior MI is present, if HTN persists, if LVD or HF is present, if diabetic adapted from Rosendorff C, et al. Circulation 2007;115:published online


Lifestyle y Modifications
Weight reduction Restriction of sodium intake Reduction in dietary fat and cholesterol Avoidance of tobacco Restriction of alcohol consumption Use of biofeedback, relaxation techniques Regular physical exercise

Lifestyle Modification
M difi ti Modification Weight reduction Adopt DASH eating plan Dietary sodium reduction Physical activity Moderation of alcohol consumption A Approximate i t SBP reduction d ti (range) 520 mmHg/10 kg weight loss 814 mmHg 28 mmHg 49 mmHg 24 mmHg

Q4: With regards to pharmacological treatment the ideal anti hypertensive is... treatment, is
With Effective BP control regardless of other attributes

With Effective BP control with evidence of CV protection

With Wi h Eff Effective i BP control, l E Evidence id of f CV protection i &

with high safety profile

Any Antihypertensive class

JNC VII: Algorithm g for Treatment of Hypertension yp

Lifestyle modifications Not at goal blood pressure (BP)* Hypertension without compelling indications Hypertension with compelling indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, -blocker, CCB) as needed

Stage 1 Thiazide-type diuretics for most May consider ACE most. inhibitor, ARB, -blocker, CCB, or combination

Stage 2 Two-drug combination for most (usually including thiazide-type diuretic)

If not at goal, optimise dosages or add additional drugs until goal BP is achieved. C Consider id consultation lt ti with ith h hypertension t i specialist i li t
*BP goal <140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease Chobanian et al. JAMA 2003;289:256072

What about BB or Diuretics?

Mancia et al. Journal of Hypertension 2009, 27:21212158

Deleterious effects of Angiotensin g II

Abnormal vasoconstriction Activate SNS S S Aldosterone Vasopressin Endothelin E d th li
SNS = Sympathetic nervous system

PAI-1/ thrombosis

Ang II

Platelet aggregation ti Superoxide production d ti

Myocyte growth

Vascular smooth muscle growth Remodeling


Burnier M, Brunner HR. Lancet. 2000;355:637-45. B Brown NJ, NJ Vaughn V h DE. DE Adv Ad I Intern t M Med d. 2000;45:419-29. 2000 45 419 29

Angiotensin II Plays a Central Role Organ ga Damage a age in O

Atherosclerosis Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction AII AT1 Receptor
LV hypertrophy

Stroke H Hypertension t i

Fibrosis Fib i Remodeling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis

Heart Failure MI


Renal Failure

*Preclinical Preclinical data. LV=left ventricular; MI=myocardial infarction; GFR=glomerular filtration rate.

Q5: RAAS Blockade is the future of Hypertension Management Do we use ACEi or ARBs? Management.



The sites of action of ACE inhibition and AT1 receptor blockade in the renin-angiotensin system

Chymase y trypsin peptidase

Angiotensin I
ACEACE -Kininase II

Angiotensin II

Inactive BK IIIId degradation d ti products receptor

AT1receptor Vasoconstriction Salt/water retention t ti Remodelling

AT2receptor AntiAnti -proliferative Cell differentiation Tissue repair


Vasodilation NatriuNatriu -/diuresis A Anti Antiti-remodelling d lli

European Heart Journal (1999) 20, 997-1008

ARBs vs. vs ACEi

Step of RAAS Blockade Bradykinin Metabolism Non ACE Pathway Activation
Receptor Level
Preserve ATII beneficial effect

Interval I t l
Deprive the body from ATII beneficial effect

Dont Interfere
No Dry Cough

Dry Cough

Non Activated

BP uncontrolled over time


Rates of Persistence With Therapy Differs Between Drug Classes

Patien nts on treatmen nt (%) 80 60 40 20 0 Persistence with antihypertensive medication at 24 months in 24,718 patients included in the Saskatchewan database


Combination Others therapy Persistence defined as prescription refill within 21 days of the target month





Lindholm. J Hum Hypertens 2002;16:S3S8

Effects of Different Antihypertensive Agents on Incidence of Diabetes

Network meta-analysis assessing the effects of different antihypertensive tih t i agents t on incidence i id of f diabetes di b t in i 48 randomised d i d groups from f 22 clinical trials* (n=143,153)
ARB ACE inhibitor CCB Placebo -blocker Diuretic 0.50 0.70 0.90 0 57 (0 0.57 (0.460.72) 46 0 72) p<0.0001 0 0001 0.67 (0.560.80) p<0.0001 0.75 ( (0.620.90) ) p=0.002 p 0.77 (0.630.94) p=0.009 0.90 (0.751.09) p=0.30 Referent 1.26 Incoherence=0.000017 Incoherence 0.000017

Odds ratio of incident diabetes *17 trials enrolled patients with hypertension, three enrolled high-risk patients and one enrolled patients with heart failure (HF) ARB=angiotensin receptor blocker; ACE=angiotensin ACE=angiotensin-converting converting enzyme; CCB=calcium channel blocker

Elliott and Meyer. Lancet 2007;369:2017

Q6: Are Drugs in the Same class Possessing the similar clinical benefits?


Pharmacological g differences
Selectivity on AT1 Receptor
30,000 ,
20000 10000
8500 1000 Valsartan Losartan irbisartan Candisartan Telmisartan 10,000 30 000 30,000


Valsartan is 30,000 , times more selective for AT1 receptors p than AT2

Clinical impact

Superior blood pressure control Proven efficacy in Endothelial dysfunction Evidence of Superior cardiovascular protection Evidence of Superior Renal protection


VALSARTAN 160 Significantly Reduces SBP by 20 mm Hg to Get Patients to Goal

Results from a 8-week study in 767 patients# with stage 2 systolic hypertension ype te s o (VALOR O study)
VALSARTAN 160 mg (n=261)

Mean change in B BP from bas seline to 8 week ks (mm Hg)


-5 -10 -15 -20 -25 -30 -20.7* -6.6

population SBP 160 and 200 mm Hg); *p<0.05 vs. baseline; p<0.05 vs. VALSARTAN 160 mg monotherapy; p<0.05 vs. DIOVAN 160 mg; Response= SBP <140 mmHg or decrease in SBP 20 mmHg after 8 weeks of treatment Lacourciere et al. Clin Ther 2005;27(7):1013 2005;27(7):1013-21 21

VALSARTAN Provides Effective BP Reductions Irrespective of Time of Administration

Results from a 3-month study in 148 non-dipper patients with mild-to-moderate essential hypertension#
VALSARTAN 160 mg o.d. Morning administration Mean c change in B BP from bas seline at 3 months s (mm Hg)
0 -2 4 -4 -6 -8 -10 -12 -14 -16 -13.1* p=NS between time of administration -14.7* -8.5* -10.3* SBP DBP

Evening administration


<10% decline in nocturnal relative to diurnal BP and SBP/DBP 140/90 and 179/109; *p<0.001 *p<0 001 vs vs. baseline Hermida et al. J Hypertens 2005;23(10):1913-1922

Tareg a eg 160 60 Reduce educe BP Beyond eyo d 24 Hours ou s

Results from a 8-week study in 256 patients with mild-to-moderate hypertension#
Mean Cha ange in SBP (mm m Hg) Mean Chan nge in DBP (mm Hg) D
15 0 5 -5

-15 -25 -35 15 0 5 -5 5

-15 -25 -35 35 2 4 6 Mean BP and 95% CI 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Time after dose administration ( (hours)* )

DBP between 95 and 115 mm Hg at baseline, *intervals 2-24, n=21 (15 treated with valsartan 80 mg, 6 with 160 mg) intervals 26-48, n=10 (9 treated with valsartan 80 mg, 1 with 160 mg), hour 25-48 without dose Lasko et al. Blood Press Monit 2001;6(2):91-99


VALSARTAN Reduces The Risk of Diabetes in Patients with High CV Risk on Monotherapy
Results from a 4.1-year study in 7,080 patients with HTN and high risk of cardiac events (VALUE study post-hoc analysis) study,
10 8 6 4 2 0 7.8% 9.9%
23% risk reduction d ti of NOD*

Rate of new-on nset diabete es ( %)

Valsartan 80-160 mg (n=3,263) (n 3,263)

Amlodipine 5-10 mg (n=3,817) (n 3,817)

UPDATED Follow-up period: 4-6 (mean 4.2) years; Patients with BP<140/90 still receiving monotherapy at the end of the 6 months up-titration; *Valsartan vs. amlodipine, p=0.012, NOD=newonset diabetes Julius et al. Hypertension 2006;48:385-391

Valsartan Reduces the Risk of New-onset Diabetes Better than Losartan

Results from a retrospective cohort study# in 14,588 patients with HTN, initiating Valsartan or losartan monotherapy for 7 years
30 Risk of f new-onset t diabetes per 1,000 patien nt-years 25 21.5 20 15 10 5 0 Valsartan (n=9,968) Losartan (n=4,620) 23% risk reduction* 27.8

#Using a US healthcare claims database; *Unadjusted risk, valsartan vs. losartan (95% CI: 0.63-0.95); newonset diabetes identified as 2 outpatient diagnoses (7 days apart), 1 inpatient diagnosis, or 1 prescriptions for antidiabetic medication Weycker et al. J Clin Hypertens 2007; Suppl A (9):P-448

Valsartan: Extensively Studied Across the Cardiovascular Continuum

Ventricular Remodelling Myocardial infarction 2 Atherosclerosis and LVH 1 4 Risk factors Diabetes Hypertension Endothelial dysfunction
*Not all patients in these studies t di received i d valsartan l t Independent, investigator-initiated study

Ventricular Dilation

Heart Failure

Includes over 50,000 patients*19

Proteinuria DROP9


End-stage Heart Disease

Death End-stage renal disease

Microalbuminuria MARVAL6 MARVAL II7 SMART8

1. Julius et al. Lancet 2004; 363:202231; 2. Pfeffer et al. N Engl J Med 2003;349:1893906; 3. Cohn et al. N Engl J Med 2001; 345:166775 4. Califf et al. Am Heart J 2008;156:62332; 5. Mochizuki et al. Lancet 2007;369:14319; 6. Viberti et al. Circulation 2002;106:6728 7. Karalliedde et al. Hypertension 2008;51:161723; 8. SMART Group. Diabetes Care 2007;30:15813; 9. Hollenberg et al. J Hypertens 2007;25:19216

Central to the success of any antihypertensive regimen
Efficacy 24-hour BP control Compliance & persistence

Factors favouring good compliance and persistence include

Once-daily dosing Tolerability

Valsartan 160 provide rapid blood pressure reduction & better

control t l throughout th h t 24 hours. h

Valsartan is the most studied ARB with evidences across the

whole CV continuum