High Risk Hypertensive Patients

Can We Do Better?
Dr. Sameh Shaheen MD, FESC, FSCAI Prof. of cardiology Ain Shams University

CASE STUDY
History:
MA is a 55-year-old male presenting to follow up his 55-yearBP. Although he has no symptoms, he has a positive family history: his mother had AMI before the age of 55. The patient has a high-stressfull job as a teacher, highleads a sedentary life, and recently stopped smoking.

Physical examination:
Weight:110 kg ; height:170 cm; waist circ: 105 cm; (BP), 150/90 mm Hg chest is clear to percussion and auscultation, regular sinus rhythm. The abdomen is free.
8

Case study
Medication:
Antihypertensive (Bisoprolol 5 mg OD). Insulin 70/30. (60 IU/day)

Laboratory data:
TC, 220mg/dL; TG, 150 mg/dL; HDL-C, 35 mg/dL; HDLLDLLDL-C, 160 mg/dL; fasting glucose level, 130 mg/dL; BUN, 18 mg/dL; SGOT and SGPT, mid-20s IU/L midrange, A1C: 7.0%, Creatinine: 1.1 mg/dL, eGFR: 69 mL/min/1.73 m2, microalbuminuria: 45 mg/24 h

Resting ECG: LVH by voltage

9

10

The ATP III guidelines

first published in 2002 and updated in 2004;

Framingham Risk scoring system

High risk: CHD or CHD risk equivalents (10-year risk for CV events> 20%) Moderately high risk: 2 risk factors (10-year risk from 10% to 20%) Moderate risk: 2 risk factors (10-year risk < 10%) Lower risk: 01 risk factor

ATP-III: Framingham Point Scores Estimate of 10-Year Risk for Men

1 Age, y
2020-34 3535-39 4040-44 4545-49 5050-54 5555-59 6060-64 6565-69 7070-74 7575-79 Points -9 -4 0 3 6 8 10 11 12 13

Systolic BP If If mm Hg Untreated Treated

5
Nonsmoker Smoker

Age Age Age Age Age 2020-39 40-49 50-59 60-69 70-79 40506070-

<120 120120-129 130130-139 140140-159 u160

0 0 1 1 2

0 1 2 2 3 Points -1 0 1 2

0 8

0 5

0 3

0 1

0 1

Point Total <0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 u17

10-Year Risk, % 10<1 1 1 1 1 1 2 2 3 4 5 6 8 10 12 16 20 25 u30

HDL mg/dL u60 5050-59 4040-49 <40

Total Cholesterol

Age 20-39 20-

Age 40-49 40-

Age 50-59 50-

Age 60-69 60-

Age 70-79 70-

<160 160160-199 200200-239 240240-279 u280

0 4 7 9 11

0 3 5 6 8

0 2 3 4 5

0 1 3 2 3

0 0 0 1 1

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. JAMA. 2001;285:2486-2497.

ESH/ESC 2007 guidelines:

12

ESH/ESC Guidelines and search for subclinical organ damage LVH EKG/Echo CA thickening / plaques

2003 GLs

SCr >1.41.5 mg/dl EKG

MicroAibuminuria

Routine

Recommended

Mentioned

2007 GLs

SCr> 1.4-1.5 mg/dl eCrCl / GFR MicroAibuminuria EKG

Assessment of target organ damage hypertension-related according to the 2003 and 2007 ESH/ESC Guidelines.

LVH EKG/Echo Concentric LVH LA enlargement CA thickening / plaques Ankle/Brachial ratio Arterial stiffening PWV*

Systolic dysfunction Diastolic dysfunction Cornary Ca++ Arteriolar remodelling Collagen markers Endothelial dysfunction Cerebral lacunae / WMLs Cognitive dysfunction Retinopathy

ESH/ESC 2007 guidelines: the impact of multiple risk factors

Normal SBP 120-129 or DBP 80-84 No other risk factors 12 additional risk factors 3 or more RF, MS, OD or Diabetes Established CV or renal disease Average risk Low added risk Moderate added risk High added risk High-normal SBP 130-139 or DBP 85-89 Average risk Low added risk High added risk Very high added risk Grade 1 SBP 140-159 or DBP 90-99 Low added risk Moderate added risk High added risk Very high added risk Grade 2 SBP 160-179 or DBP 100-109 Moderate added risk Moderate added risk High added risk Very high added risk Grade 3 SBP u180 or DBP u110 High added risk Very high added risk Very high added risk Very high added risk

Absolute added 10 year risk of cardiovascular disease: < 15% 15-20% 20-30% > 30% Framingham
1. ESH and ESC Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536./J Hypertens 2007;25:1105-1107.

14

ESH/ESC Guidelines 2007: initiaiting treatment

Normal SBP 120-129 or DBP 80-84 High-normal SBP 130-139 or DBP 85-89 Grade 1 SBP 140-159 or DBP 90-99 Lifestyle changes for several months then BP intervention if required Lifestyle changes for several months then BP intervention if required Lifestyle changes +drug treatment Lifestyle changes + immediate drug treatment Grade 2 SBP 160-179 or DBP 100-109 Lifestyle changes for several weeks then BP intervention if required Lifestyle changes for several weeks then BP intervention if required Lifestyle changes +drug treatment Grade 3 SBP u180 or DBP u110 Lifestyle changes + immediate drug treatment

No other risk factors

No treatment

No treatment

12 additional risk factors

Lifestyle changes for several months then BP intervention if required

Lifestyle changes for several months then BP intervention if required Lifestyle changes + drug treatment Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

3 or more RF, MS, OD or Diabetes Established CV or renal disease

Lifestyle changes

Lifestyle changes + immediate drug treatment Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

1. ESH and ESC Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536./J Hypertens 2007;25:1105-1107.
15

High Risk Hypertensive Patients Can We Do Better?

Q1. What is the threshold for starting antihypertensive drugs in High Risk Hypertensive Patients ? Q2. What is the BP target to reach in High Risk Hypertensive Patients ? Q3. Which drug to use in High Risk Hypertensive Patients? Patients Q4. How would you treat associated risk factors in High Risk Hypertensive Patients ?

Q1. When to initiaite antihypertensive drug therapy in low risk uncomplicated hypertension? hypertension?
Normal SBP 120-129 or DBP 80-84 High-normal SBP 130-139 or DBP 85-89 Grade 1 SBP 140-159 or DBP 90-99 Lifestyle changes for several months then BP intervention if required Lifestyle changes for several months then BP intervention if required Lifestyle changes +drug treatment Lifestyle changes + immediate drug treatment Grade 2 SBP 160-179 or DBP 100-109 Lifestyle changes for several weeks then BP intervention if required Lifestyle changes for several weeks then BP intervention if required Lifestyle changes +drug treatment Grade 3 SBP u180 or DBP u110 Lifestyle changes + immediate drug treatment

No other risk factors

No treatment

No treatment

12 additional risk factors

Lifestyle changes for several months then BP intervention if required

Lifestyle changes for several months then BP intervention if required Lifestyle changes + drug treatment Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

3 or more RF, MS, OD or Diabetes Established CV or renal disease

Lifestyle changes

Lifestyle changes + immediate drug treatment Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

1. ESH and ESC Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536./J Hypertens 2007;25:1105-1107.
17

In four out of five trials, SBP was reduced to <140 mmHg in the actively treated group while remaining at or above this value in the placebo or control group. In three out of four trials, the BP difference was associated with a difference in outcome, and in FEVER this occurred for on-treatment values that were just slightly below and slightly above 140 mmHg.

When to initiate drug treatment if patient has diabetes ??

When SBP >130 SBP mmHg or DBP >85 mmHg
Recommendations were derived from subgroup analyses of two large trials, MICROHOPE and ADVANCE.
Normal SBP 120-129 or DBP 80-84 High-normal SBP 130-139 or DBP 85-89 Grade 1 SBP 140-159 or DBP 90-99 Lifestyle changes for several months then BP intervention if required Lifestyle changes for several months then BP intervention if required Grade 2 SBP 160-179 or DBP 100-109 Lifestyle changes for several weeks then BP intervention if required Grade 3 SBP u180 or DBP u110

No other risk factors

No treatment

No treatment

Lifestyle changes + immediate drug treatment

12 additional risk factors

Lifestyle changes for several months then BP intervention if required

Lifestyle changes for several months then BP intervention if required

Lifestyle changes for several weeks then BP intervention if required Lifestyle changes +drug treatment

Lifestyle changes + immediate drug treatment

3 or more RF, MS, OD or Diabetes

Lifestyle changes

Lifestyle changes + drug treatment

Lifestyle changes +drug treatment

Lifestyle changes + immediate drug treatment

Established CV or renal disease

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

19

When to initiate drug treatment if patient has CAD??

Although no less than five trials are available, the information whether drug treatment should be initiated at high normal BP values in patients with coronary disease is INCONCLUSIVE
Normal SBP 120-129 or DBP 80-84 High-normal SBP 130-139 or DBP 85-89 Grade 1 SBP 140-159 or DBP 90-99 Lifestyle changes for several months then BP intervention if required Lifestyle changes for several months then BP intervention if required Grade 2 SBP 160-179 or DBP 100-109 Lifestyle changes for several weeks then BP intervention if required Grade 3 SBP u180 or DBP u110

No other risk factors

No treatment

No treatment

Lifestyle changes + immediate drug treatment

12 additional risk factors

Lifestyle changes for several months then BP intervention if required

Lifestyle changes for several months then BP intervention if required

Lifestyle changes for several weeks then BP intervention if required Lifestyle changes +drug treatment

Lifestyle changes + immediate drug treatment

3 or more RF, MS, OD or Diabetes

Lifestyle changes

Lifestyle changes + drug treatment

Lifestyle changes +drug treatment

Lifestyle changes + immediate drug treatment

Established CV or renal disease

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

Lifestyle changes + immediate drug treatment

MICRO-HOPE: ACEI Improves Renal and CV Outcomes in Type 2 Diabetes

N = 3577 (32% with microalbuminuria)
Overt CV nephroStroke death pathy Mean albumincreatinine ratio
3.0 2.5 2.0 22
P = 0.01

0 10

MI

Placebo
P = 0.02

Risk reduction 20 (%)

30 40

1.5 24
P = 0.027

Ramipril 10 mg
P = 0.001

1.0 0.5 0

33
P = 0.007

37
P = 0.0001

4.5

Years

HOPE Study Investigators. Lancet. 2000;355:253-9.

ACEI Outcome Trials in CAD Patients without HF:

BP at Entry/during Study
BP (mm Hg) At entry
Average BP during follow-up (active vs. placebo) HOPE 139/79 3.3/2 EUROPA 137/82 5/2 PEACE 133/78 3/1.2

SBP <140 and >130 mmHg

EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

HOPE, EUROPA, PEACE: Primary outcomes

HOPE
20 15 % Patients 10 5 0 Placebo
22% Risk reduction P = 0.001

14 12 10 8 6 4 2 0 0

EUROPA
Placebo
20% Risk reduction P = 0.0003

Ramipril 10 mg

Perindopril 8 mg

2 3 Time (years)

2 3 Time (years)

PEACE
30 25 20 % Patients 15 10 5 0 1 2 3 4 5 Time (years) 6
HOPE Study Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. 4% Risk reduction P = 0.43

Placebo Trandolapril 4 mg

Q2. What is the BP TARGET to reach in high risk hypertensive patients?

All hypertensive patients BP < 140/90 mmHg Diabetic patients (high risk) BP < 130/80 mmHg Patients with Renal Failure and proteinuria > 1g/24h BP < 125/75 mmHg

2007 ESH - ESC guidelines for the management of arterial hypertension. European Heart Journal Advance Access published June 11, 2007 JNC7 Report. JAMA 2003; 289: 2560-2572.

HOTHOT-Study: optimal blood pressure in hypertensive diabetics (Type II)

HOT = Hypertension Optimal Treatment 30

Serious cardiovascular events/1000 events/1000 pat.years

25 20 15 10 5 0

51% risk reduction

e90

e85

e80

mmHg diastolic target blood pressure

Hypertensive diabetics benefit most from tight blood pressure control

Hansson L et al. Lancet 1998;351:1755-1762.

< 135 ?? target

 SBP  SBP  SBP

<140..recommended by ESH <140.. <135..Benefits in ADVANCE <135..

<130 .Benefits confined to .B stroke (ONTARGET, INVEST) <120 .. ..No benefit (ACCORD)

 SBP

Q3. Which drug to use in high risk hypertensive patients?

Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

JNCJNC-7 Algorithm for Treatment of Hypertension

Initial Drug Choices

Without Compelling Indications Stage 1 Hypertension

(SBP 140 159 or DBP 90 99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

With Compelling Indications

Stage 2 Hypertension
(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Drug(s) for the compelling indications

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

Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

Updated UK NICE Guidelines for the Treatment of Newly Diagnosed Hypertension

<55 years Step 1 ACEI (or ARB*) u55 years or black patients at any age CCB or thiazidetype diuretic

Step 2

ACEI (or ARB*) + CCB or ACEI (or ARB*) + thiazide diuretic

Step 3

ACEI (or ARB*) + CCB + diuretic

Step 4

Add further diuretic therapy, -blocker, or -blocker. Consider seeking specialist advice

*If ACE inhibitor (ACEI) not tolerated

National Institute for Health and Clinical Excellence (NICE) (2006) Hypertension: management of hypertension in adults in primary care (Quick Reference Guide). London: NICE. Available from www.nice.org.uk/034

BMJ Meta-analysis 2009

15

Beta blockers

LIFE: Primary Composite Endpoint

0.16 0.14 0.12 Endpoint rate 0.10 0.08 0.06 0.04 0.02 0.00 0 6 12 18
Adjusted Risk Reduction 130%, p=0021 Unadjusted Risk Reduction 146%, p=0009 Intention-toIntention-to-Treat Analysis

Atenolol
( BP losartan vs atenolol: -1.1 mmHg SBP/ +0.2 mmHg DBP -0.3 mmHg MAP

Losartan

24

30

36

42

48

54

60

66 Month
901 876
Dahlf et al 2002

Losartan 4605 Atenolol 4588

4524 4460 4392 4312 4494 4414 4349 4289

4247 4189 4112 4047 3897 1889 4205 4135 4066 3992 3821 1854

CAFE: Lower central aortic BP with newer vs older antihypertensive regimen

Similar effects on brachial BP
140 Brachial SBP 135 130 mm Hg 125 120 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 Time (years) Central aortic SBP

Atenolol s bendroflumethiazide Amlodipine s perindopril

CAFE Investigators. Circulation. 2006;113:1213-25.

Which drug to use?

ESCESC-ESH 2007: Different Anti- Hypertensives in Antidifferent Sub-Clinical Organ Damage Sub-

40

ADA 2009 Recommendations

41

ACE Inhibition Reduces Oxidative Stress and Inflammation

40 Patients with type 2 diabetes
Lipid peroxides
400

TNF-E
4

IL-6

370

3.3
300

* 264

2.9

200

Qmol/L
100

pg/mL

2.0

1.8

Baseline
* P < 0.05 vs baseline

Perindopril 4 mg x 6 mos
Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A.

FACT study

PAIPAI-1 changes with Fosinopril vs Amlodipine

15

Fosinopril 40 mg 20 mg

Amlodipine 5 mg 10 mg

PAIPAI-1 change ng/mL

10 5 0 -5 -10 -15

p for trend=0.024 Fosinopril 40 mg vs. Amlodipine 10 mg p=0.29

PAIPAI-1 antigen changes versus placebo after treatment with 40 and 20 mg Fosinopril and 5 and 10 mg Amlodipine. Amlodipine.
Marco Pahor. et al. Circulation. 2002;105:457-461.

ACEIs REDUCE PLASMA FIBRINOGEN

(Double(Double-blind, randomized, cross-over) crossp=0.05

Plasma Fibrinogen (mg/dl)

p=0.022

NS

350 325 300 275 250 225 200 Perindopril 4mg Losartan 50mg
Fogari et al. J Cardiovasc Pharmacol 32:616-620

Placebo

ACEIs REDUCE PLASMA ENDOTHELIN

* p < 0.001 vs pre-Rx. CHF pts. p < 0.01 vs placebo

Galatius-Jensen et al, 1996

HOPE: Beneficial Effects of Ramipril on LV Mass and Function

Placebo 10 8 Change in LV Mass (g) 6 4 2 0 -2 -2.0 -4 -6 -3.53 p for trend = 0.03 -2.5 -2.02 p for trend = 0.01 8.21 7.86 Change in LVEF (%) -0.5 Ramipril 2.5 mg/d 0 -0.17 Ramipril 10 mg/d

-1.0

-1.5 -1.54

N=464 HOPE study patients Mean baseline LVEF 58%, all groups

Lonn E, et al. J Am Coll Cardiol 2004; 43(12):2200-6.

Major Clinical Trials of RAAS Modulation

ABCD FACET UKPDS AASK MICROHOPE PERSUADE BENEDICT RENAAL IDNT IRMA DETAIL CALM

DREAM

Aldosterone receptor blockade

Diabetes/ Pre-diabetes

NAVIGATOR

PEACE IMAGINE ONTARGET

I-PRESERVE EPHESUS

ASCOT ALLHAT ANBP2 LIFE VALUE ACTIVE-I

Atrial Fibrillation

RALES

Effective blood pressure control vs. -blockers Captopril: Effective blood pressure control in elderly hypertensive patients (p<0.01)

A crossover, double-blind study comparing the efficacy of (captopril) (25 mg bid) and bisoprolol (5 mg od) in 24 elderly patients, aged over 65 years, with mild-to-moderate essential hypertension; for 6 weeks. ref. 1
1. Bracchetti D, et al. A Double-blind Comparison of Bisoprolol and Captopril for Treatment of Essential Hypertension in the Elderly. Cardiovasc Drugs Ther 1990; 4 (1): 261-264.

Captopril: Captopril: Lower CV events vs. -blockers/ diuretics in hypertensive patients Captopril was associated with lower CV mortality compared to conventional treatment.1
A prospective, randomised, open trial with blinded endpoint evaluation comparing the effect of CAPOTEN (Captopril) (initial dose: 50 mg daily given in one or two doses; the treatment dose could be increased to 100 mg once or twice daily and if necessary a diuretic was added) or conventional antihypertensive treatment with diuretics, -blockers, or both on cardiovascular morbidity and mortality in patients with hypertension. Follow-up lasted for a mean of 6.1 years. *Cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death.Adapted from ref. 1 1. Hansson L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 61116.

AUSTRALIAN TRIAL OF ELDERLY HYPERTENSIVES

ALLHAT: Primary Endpoint

CHD Death and Nonfatal MI
16

Cumulative Events (%)

12

Chlortalidone Amlodipine Lisinopril

0 0

Years

Wright et al., JAMA 288: 2981, 2002

CV risk reduction with ACEIs in type 2 diabetes:

ABCD, CAPPP, and FACET
ACEI (n=733) vs other antihypertensive agents (n=689)
0
Acute MI CV events All-cause mortality Stroke

-10
Relative -20 risk reduction -30 (%)

-24 % P = 0.3

-40 -50 -60 -70 -63 % P < 0.001 -51 % P < 0.001 -62 % P = 0.010

Pahor M et al. Diabetes Care. 2000;23:888-892.

CAPTOPRIL Decreased risk of CV complications in diabetic hypertensives

Every 10 mm Hg decrease in mean SBP* above 120 mm Hg was associated with:

1. Adler AI, et al. Association of systolic blood pressure with macrovascular and microvascular complications 1. of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412-9. 2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment 2. of High Blood Pressure. NIH Publication 2004.

Renal impairment is a common complication in diabetic hypertensive patients

26%

of hypertensive patients with type II

diabetes have chronic kidney disease.1

1.

Ravera M, et al. Chronic kidney disease and cardiovascular risk in hypertensive type 2 diabetics: a primary care perspective. Nephrol Dial Transplant 2008

Cardiovascular Morbidity and Proteinuria

40 Cumulative incidence (%) of CV morbidity

Proteinuria
p < 0.001

30

20 No Proteinuria 10

0 0 1 2 3 4 5 6 Years 7 8 9 10
Adapted from Samuelsson et al. J Hypertens 1985;3:72

Effect of Captopril in Patients with Type 1 Diabetes and Nephropathy

The Effect of ACEI on Diabetic Nephropathy
Edmund J. Lewis, Lawrence G. Hunsicker, Raymond P. Bain, Richard D Rohde, for The Collaborative Study Group

Type I diabetes

Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups. Panel A shows the cumulative percentage of patients with the primary end point: a doubling of the base-line serum creatinine concentration to at least 2.0 mg per deciliter. Panel B shows the cumulative percentage of patients who died or required dialysis or renal transplantation.

50% RRR

Effective reduction of renal complications in hypertensive type II diabetic patients

Captopril: Effective reduction in urinary albumin excretion rate vs. -blockers/diuretics in hypertensive type II diabetic patients

A prospective, double-blind, randomized trial comparing the effect of CAPOTEN (Captopril) monotherapy (25 mg bid) or combined with hydrochlorothiazide vs. metoprolol (50 mg bid), hydrochlorothiazide (12.5 mg bid), or both on albuminuria in 21 patients with hypertension, type II diabetes and microalbuminuria for 36 months. Adapted from ref. 1 1. Lacourcire Y, et al. Captopril or Conventional Therapy in Hypertensive Type II Diabetics: Three-Year Analysis. Hypertension 1993; 21: 786-79

Effective reduction of renal complications in hypertensive type II diabetic patients

Captopril: Effective reduction in urinary albumin excretion rate vs. -blockers/diuretics in hypertensive type II diabetic patients

A prospective, double-blind, randomized trial comparing the effect of CAPOTEN (Captopril) monotherapy (25 mg bid) or combined with hydrochlorothiazide vs. metoprolol (50 mg bid), hydrochlorothiazide (12.5 mg bid), or both on albuminuria in 21 patients with hypertension, type II diabetes and microalbuminuria for 36 months. Adapted from ref. 1
1. Lacourcire Y, et al. Captopril or Conventional Therapy in Hypertensive Type II Diabetics: Three-Year Analysis. Hypertension 1993; 21: 786-79

Effect of ACE inhibitor therapy started in the acute phase (036 h) of myocardial infarction and continued for a short time (46 weeks) on cumulative mortality during days 030 in all trials combined: systematic overview of individual data from 100 000 patients in randomized trials

Potential Impact of CV-protective Medication Class in Post-MI Patients

Improving quality of care, quality of life Medication class None Aspirin F-Blocker ACE inhibitor Lipid lowering RRR (%) 0 25 25 25 30 5-Year CV-event risk (%) 20.0 15.0 11.3 8.4 5.9

Cumulative risk reduction if all 4 medication classes are used: ~70% NNT to prevent 1 major CV event in 5 years: 7
Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):S37-46.

EUROPA
% CV death, MI or cardiac arrest
14 12 10 8 6 4 2 0
0 1 2 3 4 5 Years

Placebo Perindopril

RRR: 20% 20% p = 0.0003

Placebo annual event rate: 2.4%

RAS inhibition in CV Disease

JNC 7: ACEIs, the only class recommended irrespective of patients risk profile.

Average Number of Antihypertensive Agents Needed Per Patient to Achieve Target SBP Goals
Trial (SBP achieved) ASCOT-BPLA (136.9 mmHg) ALLHAT (138 mmHg) IDNT (138 mmHg) RENAAL (141 mmHg) UKPDS (144 mmHg) ABCD (132 mmHg) MDRD (132 mmHg) HOT (138 mmHg) AASK (128 mmHg)
1

Number of medications

Bakris et al. Am J Med 2004;116(5A):30S8 74 Dahlof B, et al. Lancet 2005;366:895906

Current Treatment Guidelines Recognize the Need for Multiple Medications

JNC VII1
Most patients with hypertension will require two or more antihypertensive agents to achieve their BP goals When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with 2 drugs, either as separate prescriptions or in fixedfixed-dose combinations

ESH ESHESC2
To reach target blood pressures, it is likely that a large proportion of patients will require therapy with more than one agent
1. Chobanian et al. JAMA 2003;289:256072 75 2. ESHESC Guidelines. J Hypertens 2003;21:101153

Single-pill Combinations Improve Compliance Regardless of Concomitant Medications

Medication-possession ratio (MPR) 100% 90% 80% 70% 60% 50% 1 2 3 4 5 6 Number of concomitant drugs >6
85.9% 87.3% 86.5% 88.8% 87.7% 89.6% 90.2%

73.7%

73.6%

72.1%

70.1%

69.7%

67.2%

65.6%

Single-pill combination (n=2,839)

*p<0.0001

Free combination (n=3,367)

Gerbino PP, Shoheiber O. Am J Health System Pharm 2007;64:127983

Better Compliance with Antihypertensive Drugs Leads to a Decreased Risk of Hospitalization

50

All-cause hospitalization risk (%)

44* 39

*
36

40 30 20 10 0 119
(n=350)

*
30

*
27

2039
(n=344)

4059
(n=562)

6079
(n=921)

80100
(n=5,804)

Level of compliance (%)

*p<0.05 vs 80100% compliant group Sokol et al. Med Care 2005;43:52130

The value of combination therapy in high risk patients

y A recent meta-analysis of 42 metastudies has shown that combining two agents from any two classes of antihypertensive drugs increases the BP reduction much more than doubling the dose of one agent.

The EARLY use of combination therapy as FIRST STEP treatment in high risk patients
y In high-risk patients, an event may occur within a relatively short time interval y The protective effect of BP reduction became manifest shortly after initiation of treatment y Combination therapy can reduce BP to a greater extent and achieve goal more promptly y Combination treatment may be associated with a lower degree of treatment discontinuation

VALUE : Odds Ratios Over Time

Time (months) ( SBP (mmHg)

Primary Endpoint

all study 0-3 3-6 6-12 12-24 24-36 36-48 study end

2.2 3.8 2.3 2.0 1.8 1.6 1.4 1.7

Favours Valsartan 0.5 Favours Amlodipine

1.0 2.0 Odds Ratio Julius S et al. Lancet. June 2004;363.

yIn a post hoc analysis of the VALUE trial the CV event trial, rate was less regardless of the type of treatment in patients in whom BP control (140/90 mmHg) was achieved within 1 month.

What type of combination?

ESH ESHESC Guidelines 2003 vs. 2007

Diuretics

Diuretics

2003
-B ARB -B

2007
ARB

E-B

CCB E-B

CCB

ACE-I
preferred combinations

ACE-I
ESHESC Guidelines. J Hypertens 2003;21:101153 Slide Source Hypertension Online ESHESC Guidelines. J Hypertens 2007;25:110587 www.hypertensiononline.
org

US and European Guidelines Agree on Additional Benefit From Use of Angiotensin Receptor Antagonists
Class Conditions favoring use (ESH-ESC) Compelling indication (JNC 7)

Diuretic (thiazide) -blockers Calcium antagonists ACE-inhibitors

CHF, elderly, ISH, African origin Angina, post-MI, CHF, pregnancy, tachyarrhythmias Elderly, ISH, angina, PVD, carotid atherosclerosis, pregnancy CHF, LVSD, post-MI, non-diabetic nephropathy, type 1 diabetic nephropathy, proteinuria Type 2 diabetic nephropathy, diabetic microalbuminuria, proteinuria, LVH, ACE-inhibitor cough BPH, hyperlipidemia

CHF, high coronary risk, diabetes, stroke prevention CHF, post-MI, diabetes, stroke prevention High coronary risk, diabetes CHF, post-MI, high coronary risk, diabetes, chronic kidney disease, recurrent stroke prevention CHF, diabetes, chronic kidney disease

Angiotensin II receptor blockers

-blockers

ISH isolated systolic hypertension; CHF chronic heart failure; LVH left ventricular hypertrophy; PVD peripheral vascular disease; LVSD left ventricular systolic dysfunction; BPH benign prostatic hyperplasia

ACE inhibitors plus Diuretics

RAAS Blocker + Diuretic*

Targets two key mechanisms of action

Salt/volume Neurohormonal

Additive efficacy Excellent BP reduction in many demographic groups Potential safety/ tolerability benefits
RAAS=renin-angiotensin-aldosterone system CCB=calcium channel blocker; BP=blood pressure *Versus either drug alone Weir MR. Am J Hypertens 1998;11:163S169S.

ESH ESHESC Guidelines 2003 vs. 2007

Diuretics Diuretics

2003
-B ARB -B

2007
ARB

E-B

CCB E-B

CCB

ACE-I
preferred combinations

ACE-I
ESHESC Guidelines. J Hypertens 2003;21:101153 Hypertension Online www.hypertensiononline. ESHESC Guidelines. J Hypertens 2007;25:110587 org
Slide Source

Captopril + HCTZ : Effective blood pressure control vs. B-blocker/diuretic combination

A randomized study comparing the efficacy of captopril (25-50 mg 3 times daily) and atenolol (50-100 mg once daily) in 25 patients with essential hypertension and evaluating the efficacy of adding hydrochlorothiazide (25-50 mg) to those who did not become normotensive (supine diastolic blood pressure less than 95 mm Hg) on captopril or atenolol alone. ref. 1
Hydrochlorothiazide.1. Andrn L, et al. Captopril or atenolol in essential hypertension. Acta Med Scand Suppl 1983; 677: 115-8.

Proven efficacy in hypertension management

Captopril + HCTZ: Effective blood pressure control vs other ACEI/diuretic combinations in mild to moderate hypertension
A double-blind, randomized, parallelgroup study comparing the efficacy of captopril 50 mg plus hydrochlorothiazide 25 mg once daily and enalapril 20 mg plus hydrochlorothiazide 12.5 mg once daily in the management of mild to moderate black hypertensive patients; for 12 weeks.1
Hydrochlorothiazide. ** Angiotensin-converting-enzyme inhibitor. *** Sitting diastolic blood pressure. 1. Skoularigis J, et al. Comparison of captopril-thiazide and enalapril-thiazide combinations in the management of mild to moderate black hypertensive patients: how important is diuretic dose and duration of action of the ACE-inhibitor?. Int J Clin Pharmacol Ther 1996; 34 (6): 263-8. 2. Critchley JAJH, et al. A randomized, double-masked comparison of the antihypertensive efficacy and safety of combination therapy with losartan and hydrochlorothiazide versus captopril and hydrochlorothiazide in elderly and younger patients. Current Therapeutic Research 1996; 57 (5): 392-407.

Captopril + HCTZ: Effective BP control vs. ARB/diuretic combinations

A randomized, double-masked trial comparing antihypertensive efficacy of captopril 50 mg /hydrochlorothiazide 25 mg (once daily) and losartan 50 mg/hydrochlorothiaz ide 12.5 mg (once daily) in elderly and younger patients with mild-tomoderate essential hypertension for 12 weeks. ref. 1
Hydrochlorothiazide. *Angiotensin receptor blocker. **Sitting diastolic blood pressure. 1. Critchley JAJH, et al. A randomized, double-masked comparison of the antihypertensive efficacy and safety of combination therapy with losartan and hydrochlorothiazide versus captopril and hydrochlorothiazide in elderly and younger patients. Current Therapeutic Research 1996; 57 (5): 392-407.

Once daily for 24 hr BP control

Captopril + HCTZ: Once daily for 24 hr BP control in most patients with mild to moderate essential hypertension With Captopril 50 mg + HCTZ 25 mg given once daily, a sustained 24 h reduction of BP can be seen and no rebound of blood pressure is observed during the night or early in the morning.1
1. Meijer JL, et al. Captopril plus hydrochlorothiazide once daily normalizes 24 h blood pressure in patients with essential hypertension. Br J clin Pharmac 1987; 23: 83S-88S.

Favorable tolerability profile

Captopril: Favorable tolerability profile vs. CCB (amlodipine)

A double-blind, parallel, comparative study of the antihypertensive efficacy and safety of twice-daily oral doses of Captopril (25-50 mg) vs. once-daily oral doses of amlodipine (5-10 mg) in adult patients with mild or moderate essential hypertension. ref. 1
1. Velasco M, et al. A double-blind, parallel, comparative evaluation of amlodipine vs. captopril in the monotherapeutic treatment of mild and moderate essential hypertension. J Cardiovasc Pharmacol 1991; 17 (Suppl 1): S19-21.

Proven tolerability profile

CAPOZIDE (Captopril + HCTZ): Favorable tolerability profile vs. CCB* (nifedipine)

A randomized study comparing the safety of captopril plus hydrochlorothiazide (HCTZ) 25/15 mg and nifedipine gastrointestinal therapeutic system (GITS) 30 mg for up to 12 weeks (upward dose titration was permitted at weeks 3 and 6) in 145 patients with mild to moderate hypertension. ref. 1
Hydrochlorothiazide. *Calcium channel blocker. 1. Weir MR, et al. Safety and Efficacy of Once-Daily Captopril Plus Hydrochlorothiazide versus Nifedipine Gastrointestinal Therapeutic System in Black Patients with Mild to Moderate Hypertension. Am J Ther 1996; 3 (12): 811-817.

High tolerability profile

Captopril + HCTZ: Favorable tolerability profile in mild to moderate hypertension

The efficacy and safety profile of Captopril + HCTZ makes it an ideal therapeutic agent for the management of mild and moderate hypertension.
A randomized, double-blind, parallel-group study comparing the safety of captopril-hydrochlorothiazide (25/25 mg o.d; after 4 weeks, the doses were mandatorily increased to captopril-hydrochlorothiazide, 50/25 mg o.d., and treatment continued for a further 4 weeks) and felodipine-metoprolol (5/50 mg o.d.; after 4 weeks, the doses were mandatorily increased to felodipine-metoprolol, 10/100 mg o.d., and treatment continued for a further 4 weeks) in the treatment of patients with mild to moderate hypertension.1
1. Klein G. Combination therapy with felodipine and metoprolol compared with captopril and hydrochlorothiazide. German MC Study Group. Blood Press 1998; 7 (5-6): 308-12. 2. Andersen H, et al. Efficacy of captopril and hydrochlorothiazide administered once a day. Postgrad Med J 1986; 62 (Suppl 1): 146-9.

Captopril: Captopril: Neutral effects on erectile function

Up to 58% of hypertensive males experience one or more
symptoms of sexual dysfunction of varying degrees of severity during antihypertensive drug therapy.1

65.9%
of patients who took blockers (atenolol, metoprolol or bisoprolol) had exhibited erectile dysfunction (ED).2

While...
effects on erectile function.

Angiotensin-converting enzyme inhibitors seem to have neutral

3

1. Ferrario CM, Levy P. Sexual Dysfunction in Patients with Hypertension: Implications for Therapy. J Clin Hypertens 2002; 4 (6): 424-432. 2. Doumas M, et al. Beneficial effects of switching from -blockers to nebivolol on the erectile function of hypertensive patients. Asian Journal of Andrology 2006; 8 (2): 177-182. 3. Doumas M, Douma S. The effect of antihypertensive drugs on erectile function: A proposed management algorithm. The Journal of Clinical Hypertension 2006; 8 (5): 359-364.

Captopril: Captopril: Beneficial or no effects on lipid metabolism

Elevation of serum triglycerides (TG) and lowering of highhighdensity lipoproteins (HDL) seen during betabetablocker therapy might counteract the effect upon mortality and number of cardiovascular complications.1 complications.1

1. Frithz G, Weiner L. Effects of Bisoprolol on Blood Pressure, Serum Lipids and HDL-Cholesterol in Essential Hypertension. Eur J Clin Pharmacol 1987; 32: 77-80. 2. Fogari R, et al. Effects of different beta-blockers on lipid metabolism in chronic therapy of hypertension. Int J Clin Pharmacol Ther Toxicol 1988; 26 (12): 597-604. 3. Pollare T, et al. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989; 321 (13): 868-73.0

Captopril + HCTZ: Long-term effect Longon serum cholesterol

Serum cholesterol values recorded during placebo and after treatment with hydrochlorothiazide or with the combination hydrochlorothiazide + captopril. * p < 0.05, ** p < 0.01, *** p < 0.001 in comparison with placebo period (month 0) within each group of patients.

1. Ambrosioni E, et al. Captopril and hydrochlorothiazide: rationale for their combination. Br J clin Pharmac 1987; 23: 43S-50S.

Captopril + HCTZ: Long-term Longeffect on serum glucose

In a 2-year study Captopril-thiazide combination does not produce any of the unwanted metabolic effects which can be observed by administering thiazides alone.1
Serum glucose values recorded during placebo and after treatment with hydrochlorothiazide or with the combination hydrochlorothiazide + captopril. p < 0.05, in comparison with placebo period (month 0) within each group of patients.1
1. Ambrosioni E, et al. Captopril and hydrochlorothiazide: rationale for their combination. Br J clin Pharmac 1987; 23: 43S-50S.

Effects of Different Antihypertensive Agents on Incidence of Diabetes

Network meta-analysis assessing the effects of different antihypertensive agents on incidence of diabetes in 48 randomised groups from 22 clinical trials* (n=143,153)
ARB ACE inhibitor CCB Placebo -blocker Diuretic 0.50 0.70 0.90 0.57 (0.460.72) p<0.0001 0.67 (0.560.80) p<0.0001 0.75 (0.620.90) p=0.002 0.77 (0.630.94) p=0.009 0.90 (0.751.09) p=0.30 Referent 1.26 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-converting enzyme; CCB=calcium channel blocker

Elliott and Meyer. Lancet 2007;369:2017

98

Effect of antihypertensives on insulin sensitivity (Kaplan et al)

Would you give antiplatelets?

Antiplatelet therapy, in particular low-dose lowaspirin, should be prescribed to hypertensive patients with previous cardiovascular events; It can also be considered in hypertensive patients without a history of cardiovascular disease with reduced renal function or with a high cardiovascular risk. In patients receiving aspirin, careful attention should always be given to the increased possibility of bleeding, particularly gastrointestinal.

Median A1C and Interquartile Ranges A1

1.41%/yr 1.14%/yr HR = 1.22 (1.01-1.46) P = 0.04

Would you give a statin? statin?

Major cardiovascular event rates in subjects randomized to active treatment or to placebo in statin trials in primary prevention.

EHS/ESC 2007 guidelines

Consider statin therapy in hypertensive patients who have an estimated 10-year risk of 10cardiovascular events more than 20% Statin benefits can be observed also in patients with elevated CRP and at moderate cardiovascular risk (about 15% cardiovascular events in 10 years).

ADA 2009 Recommendations for Hypertensive Dyslipidemic Patient

106

Take Home Message

Risk stratification of hypertensives should include assessment of associated risk factors and target organ damage The BP goal in non-complicated HTN is 140/90 and130/80 in HTN with DM or with established CV or renal disease ACE inhibitors are first line therapy in hypertension with proven reduction of CV events. In hypertensives with DM and microalbuminuria, ACE inhibitors delay progression to macroalbuminuria ; they reduce mortality in patients with diabetic nephropathy. ACEI are recommended early post AMI, in advanced heart failure and in patients with chronic stable CAD Other risk factors like DM and dyslipidemia should be adequately controlled.

..In High Risk Hypertension: Initiate drug therapy at 130/85 mmHg (threshold) Reduce the BP to

<130/80 mmHg (target)

Use of combination therapy Early ACEI + thiazide is among the recommended combinations Treat associated risk factors

Thank you

THANK YOU