DIFFERENTIAL EFFECTS OF BLOOD PRESSURE

MEDICATIONS IN BLACK PATIENTS

Jackson T. Wright, Jr. MD, PhD

Professor of Medicine

Program Director,

WT Dahms MD Clinical Research Unit

Clinical and Translational Science Collaborative

Director, Clinical Hypertension Program

University Hospitals Case Medical Center

Presenter Disclosure Information

FINANCIAL DISCLOSURE:

Research support: NIH

Consulting: Novartis, Takada, Sanofi-Aventis, CVRx,

NIH

Jackson T. Wright, Jr, MD, PhD

UNLABELED / UNAPPROVED USES DISCLOSURE:

None

RACE IN MEDICINE

• Definition not standardized

– Usually defined by self-identification in research studies

– Unless participant questionnaire utilized or telephone survey, often have little assurance that all participants are actually asked the question

– Especially a problem for retrospective studies where method of ascertainment often not defined

• Racial differences usually confounded by SES which usually cannot be adequately adjusted for statistically

• However, racial differences are often sufficiently large that ambiguity in the definition of race is unlikely to account for these differences

RACE IN MEDICINE

• Some have suggested that race is a social construct, BUT it does have biological consequences

– Blacks have a higher rate of complications all of the major causes of death and hospitalization, including CVD, many cancers, infectious diseases, etc.

– A Black child born today has the life-expectancy of a White child born 30-35 yrs ago and is twice as likely to die in the first year of life

• Racial differences often confused with geneticdifferences; however genetics is only one (and probably least important explanation)

RACE IN MEDICINE

– Clinically significant differences in disease presentation, pathophysiologic characteristics and response to treatment are evident by race and ethnicity

– Evaluation of disease differences in subsegments of the population is essential to understand the variation in pathophysiological mechanisms

– The study of population differences may provide valuable information on the disease in the affected population but is also likely to benefit the overall population

Increased Complications in Black

Hypertensive Patients

Cause of death in 30% African American males and 20% Black females

Nonfatal strokes — 30% than in whites

Fatal strokes — 80% than in whites

Heart disease deaths — 50% than in whites and occurs at younger age

Kidney failure — 400% than in whites (HTN-related — up to 2000% greater)

Prevalence of HTN in African- and European-

Origin Populations*

Pre

vale

nce o

f

Hyp

ert

en

sio

n,

%

*Age-adjusted.Cooper RS et al. BMC Medicine. 2005;3:2.

0

10

20

30

40

50

60

Average BMI

Adapted from Cooper R, et al. Am J Public Health. 1997;87:166.

Nigeria

Cameroon

(rural)

Cameroon

(urban)

Jamaica

St. LuciaBarbados

Maywood, IL

22 24 26 28 30 32

10

15

20

25

30

35

Prevalence of HTN

Among the African DiasporaP

erc

en

tag

e o

f P

op

ula

tio

n

Development of Antihypertensive Therapies

Direct

vasodilators

-blockers DRIs

Peripheral

sympatholytics

Ganglion

blockers

Veratrum

alkaloids

Central 2

agonists

Calcium

antagonists-

non DHPs

-blockers

Thiazide

diuretics

Calcium

antagonists-

DHPs

ARBs

1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2002

ACE

inhibitors

Effectiveness

Tolerability

Hypertension Treatment by Drug Class

0

10

20

30

40

50

60

1978 1981 1984 1987 1990 1993 1996 1999 2002

Year

% o

f T

reate

d P

ati

en

ts o

n M

ed

icati

on

CCBs

ß-Blocker

ACE Inhibitors

Diuretics

ARBs

IMS Health NDTI, 1978-2002

The reason to prescribe a treatment is that

there is good evidence that it provides

benefit

NOTthat there is insufficient evidence that it

does not

THIS IS PARTICULARLY TRUE IN

POPULATIONS (LIKE BLACKS)

AT HIGHEST RISK

RENIN ANGIOTENSIN SYSTEM (RAS)

INHIBITORS

• Angiotensin converting enzyme (ACE)-

Inhibitors

• Angiotensin Receptor Blockers (ARBs)

• Direct Renin Inhibitors (DRIs)

• (Beta Blockers)

HISTORY OF RAS INHIBITOR USE IN US

RAS inhibitors leading class of CV medications since the early 80’s (> $7 billion/yr market)

During much of their history on the market, industry avoided studies containing significant numbers of Blacks

It more commonly generously supported programs and speakers aimed at promoting their use

Lessened efficacy of β-blockers and ACEIs lowering BP in Black hypertensives not appreciated for 10 yrs after introduction

Efficacy of ACEI on renal disease not available in Blacks for 8 yrs after proven effective in non-Blks

A-level evidence still missing for both β-blockers and ACEIs in Blacks for CHF

BP Response Rates in VA Trial

by Race

0

10

20

30

40

50

60

70

80

0

10

20

30

40

50

60

70

80

DILT HCTZ CLON PRAZ ATEN PLAC CAPT ATEN DILT CAPT CLON HCTZ PRAZ PLAC

64

53

58

43

45

42

38

48

33

45

24

42

20

45

68

56

64

52

60

55

58

60 59 56 63

5248

32

Pa

tie

nts

wit

h R

es

po

ns

e (

%)

Pa

tie

nts

wit

h R

es

po

ns

e (

%)

Materson, B. J. et. al. N Engl J Med 1993;328:914-921

Older Blacks Older Whites

White’s n = 2046

Black’s n = 533

Frequency Distribution SBP in Response to Quinapril in

Black and White Participants (E. Mokwe et. al., HTN 2004;43:1)

Decrement in Blood Pressure

Ashwini R. Sehgal, Hypertension 2004; 43;566-572.

Mean Black-White Difference in

mmHg (CI)

4.6 (2.7-6.5)/3.0 (1.9-4.1)

HOPE TrialHeart Outcomes Prevention Evaluation

Ramipril Vs Placebo in 9,541 High CV Risk Participants

HOPE Investigators. NEJM 2000; 342:145

Event(s) Risk Reduction

CV deaths + MI + stroke 22%

CV death 25%

Nonfatal MI 20%

Nonfatal stroke 32%

Revascularization 15%

CHF hospitalizations (#) 16%

New-onset diabetes 30%

Representation of Blacks in Major

CVD/DM/Renal Clinical Trials

Trial Year # Blacks (%) Trial Year # Blacks (%)

ALLHAT 2002 15,133 (35.6%) SOLVD/Rx 1991 394 (15.3%)

AASK 2002 1,094 (100%) TONE 1998 234 (24.0%)

A-HeFT 2004 1,050 (100%) IDNT 2001 228 (14%)

HDFP 1979 4,846 (44.3%) RENAAL 2001 227 (15%)

SHEP 1991 657 (13.9%) HOPE 2000 ~175 (1.8%)

VA Coop 1967 77 (53.8%) UKPDS 1998 87 (7.6%)

VA Coop 1970 380 (41.3%) MDRD 1995 66 (7.9%)

ACCOMPL 2008 1,416 (12%) ABCD 1998 65 (13.8%)

HOT 1998 582 (3.1%) MRFIT 1985 926 (7.2%)

LIFE 2002 533 (5.8%) ELITE 1997 34 (4.7%)

VALUE 2004 490 (2.7%) CAPT-DM 1993 30 (7.3%)

ASCOT 2005 ~960 (5%)* DREAM 2006 <5%

AASK Clinical Endpoint Analysis

ACEI vs. CCB ACEI vs. BB

Outcome

% Risk

Reduction1

95 %

Confidence

Interval

% Risk

Reduction

95 %

Confidence

Interval

GFR event,

ESRD or Death2

38% (+ 14 to + 55)

p<0.005

22% (+ 1 to + 38)

p< 0.042

GFR event or ESRD3 40% (+ 13 to + 59)

p<0.007

22% (- 1 to + 41)

p< 0.066

ESRD or Death4 48% (+ 26 to + 65)

p<0.004

21% (- 5 to + 40)

p< 0.11

ESRD alone5 59% (+ 34 to + 74)

p< 0.001

23% (- 10 to + 45)

p< 0.14

1) Adjusted for baseline proteinuria, MAP,gender, Hx CHF and age; 2) 179 declining GFR, 84 ESRD,

77 death; 3) 170 declining GFR, 84 ESRD; 4) 171 ESRD, 79 deaths; 5 170 events, deaths censored.

Wright et al 2002; JAMA, 288:2421

Blood Pressure During Follow-up

Ramipril Amlodipine Metoprolol

Low

MAP

Goal

Usual

MAP

Goal

SBP

(mm Hg)

134 131 134 128* 141

DBP

(mm Hg)

81 81 81 78* 85

MAP

(mm Hg)

99 98 99 94* 104

*Significantly different between two blood pressure goals P<0.01

Wright et al. JAMA. 2002;288:2421.

0 1 2 3 4 5 6 7 8 9 10

01

02

03

04

050

60

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-up Time (Years)

Number at Risk: 1094 1064 986 918 831 739 635 555 490 331 176

Cumulative Incidence of Events

(Doubling SCr, ESRD, or Death)

Only Trial Only Post-TrialMixed Trial and Post-Trial

ESRD or

Doubling SCr

Death

Composite

AASK Grp.

Arch Intern Med

2008;168:832

Only Trial Mixed Trial and Post-Trial Only Post-Trial

Number At Risk

Usual BP & non-ACEI:

Low BP and ACEI:

Non-ACEI with

Usual BP

ACEI with

Low BPCu

mu

lati

ve I

ncid

en

ce (

%)

0

10

20

30

40

50

60

Follow-Up Time (Years)

0 1 2 3 4 5 6 7 8 9 10

104 63 23130 120168 151273

196 183

293215333

210

324

Cumulative Incidence of Events in (1) ACEI with Low BP Group and

(2) Non-ACEI with Usual BP Groups

42,418 high-risk

hypertensive patients90% previously treated

10% untreated

STEP 1 AGENTS

Chlorthalidone12.5-25 mg

Amlodipine2.5-10 mg

Lisinopril10-40 mg

Doxazosin1-8 mg

Non-Blacks: 9,886 Blacks: 5,369 Non-Blacks: 5,844 Blacks: 3,210

STEP 2 AND 3 AGENTS (5 years)

Atenolol

28.0%

Clonidine

10.6%

Reserpine

4.3%

Hydralazine

10.9%

Hypertension TrialALLHAT

Chlorthalidone Amlodipine Lisinopril

SBP – mean (sd)

Black 135.0 (15.8) 136.1 (15.3) 139.1 (19.7)

Non-

black133.3 (14.8) 133.8 (14.6) 134.2 (16.7)

DBP – mean (sd)

Black 77.4 (10.0) 76.3 (10.1) 78.0 (11.4)

Non-

black74.4 (9.5) 73.6 (9.6) 74.1 (10.1)

∆ BP compared

with

chlorthalidone

Black --- +1.1 / -1.1* +4.1* / +0.6

Non-

black--- +0.5 / -0.8* +0.9 / -0.3

Blood Pressure at 5 Years

by Race

*P<0.005

ALLHAT

Wright JT et al. JAMA 2005; 293:1593

ALLHAT Black vs. Non-BlackLisinopril/Chlorthalidone

Relative Risk and 95% Confidence Intervals

Nonfatal MI + CHD Death

All-Cause Mortality

Combined CHD

Combined CVD

Stroke

End Stage Renal Disease

Heart Failure

Black

Favors

Lisinopril

Favors

Chlorthalidone

0.50 1 2

1.30 (1.10 - 1.54)

1.30 (0.94 - 1.75)

1.40 (1.17 - 1.68)

1.19 (1.09 - 1.30)

1.15 (1.02 - 1.30)

1.06 (0.95 - 1.18)

1.10 (0.94 - 1.28)

Non-Black

Favors

Lisinopril

Favors

Chlorthalidone

0.50 1 2

1.13 (1.00 - 1.28)

0.93 (0.67 - 1.30)

1.00 (0.85 - 1.17)

1.06 (1.00 - 1.13)

1.01 (0.93 - 1.09)

0.97 (0.89 - 1.06)

0.94 (0.85 - 1.05)

Wright JT et al

JAMA 2005;

293:1593

SummaryLisinopril vs. AmlodipineALLHAT

Non-Blacks Blacks

SBP Control <+0.5 mmHg + 2-3 mmHg

# antihypertensive drugs similar + 0.3

Combined CHD, Mortality,

ESRD, cancer

similar similar

Stroke similarbut men -11%, women +46%

+ 45%

Combined CVD

HF

hospitalized angina

PAD

similar

- 15%

similar

+ 18%

+ 13%

- 11%

+ 26%

+ 22%

GI Bleed + 16% + 28%

Angioedema > >>

+favors amlodipine

- favors lisinopril Leenen F,et.al. Hypertens 2006;48:1

ANGIOEDEMA

Total Blacks

Non-

blacks

Chlorthalidone 8 / 15,255

0.1%

2 / 5,369

<0.1%

6 / 9,886

0.1%

Lisinopril 38 / 9,054

0.4%

23 / 3,210

0.7%

15 / 5,844

0.3%

P<0.001 P<0.001 P=0.002

There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to

chlorthalidone not significant).

ALLHAT

0 180 360 540 720 900 1080 1260 1440 1620 1800 1980Study Day0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16E

nd

po

int

Rate

Intention-to-Treat

Losartan

Atenolol

LIFE: Primary Composite Endpoint

Study Month 0 6 12 18 24 30 36 42 48 54 60 66Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted Risk Reduction 13·0%, p=0·021

Unadjusted Risk Reduction 14·6%, p=0·009

B Dahlof et al. Lancet 2002;359:995-1003

Results of Primary Composite Endpoint in

LIFE by Ethnic Group

Results of primary composite end point by

ethnic group. The dots represent the hazard

ratio; dot size is proportional to the number of

patients for each ethnic group, as shown to the

left. The line through each dot corresponds to

the 95% confidence interval.

Results of primary composite end point by

ethnic group in the U.s.: blacks versus non-

blacks.

Julius et al. J Am Coll Cardiol. 2004;43:1047-55.

J Hypertens 2006;24:2163

Figure 2

Biochemical Results –

Fasting Glucose – mg/dL

Chlorthalidone Amlodipine Lisinopril

Total –mean (SD)

Baseline 123.5 (58.3) 123.1 (57.0) 122.9 (56.1)

4 Years 126.3 (55.6) 123.7 (52.0) 121.5 (51.3)*

Among baseline nondiabetics with baseline <126 mg/dL – mean (SD)

Baseline 93.1 (11.7) 93.0 (11.4) 93.3 (11.8)

4 Years 104.4 (28.5) 103.1 (27.7) 100.5 (19.5)*

Diabetes incidence (follow-up fasting glucose 126 mg/dl)

4 Years 11.6% 9.8%* 8.1%*

*P<0.05 compared to chlorthalidone

ALLHAT

DREAM

RAS Blockade & New Diabetes(Diabetes - Not Primary Outcome)

Study N (no DM) Active Control RRR

ACE Inhibitors

HOPE 5720 Ramipril 10 OD Placebo 34%

PEACE 6174 Trandolapril Placebo 17%

EUROPA 10716 Perindopril 8 mg Placebo 3%

D-SOLVD 291 Enalapril Placebo 74%

Angiotensin Receptor Blockers

SCOPE 4368 Candesartan 16/d Placebo 20%

CHARM 5436 Candesartan 4-32/d Placebo 24%

Overall Effect (HOPE, EUROPA, PEACE): 0.86 (0.78-0.95)Dagenais et al. Lancet 2006;368:581

Stamler J et al. Diabetes Care. 1993;16:434-444.

Elevated SBP increases risk of CV death almost twofold in diabetic vs nondiabetic patients

Ca

rdio

va

sc

ula

r M

ort

ality

Ra

te p

er

10

,00

0 P

ati

en

t-Y

ea

rs

SBP (mm Hg)

Nondiabetic patients

Diabetic patients

250

200

150

100

50

0<120 120–139 140–159 160–179 180–199 200

MRFIT20

Elevated SBP in Type 2 Diabetes Increases Cardiovascular Risk

DREAM

Metabolic Changes

Baseline 4 Years

A B A B

Serum cholesterol,

mg/dl

216 215 197 187

Serum potassium,

mmol/l

4.3 4.4 4.1 4.4

Fasting serum

glucose, mg/dl

123 122 125 117

Serum creatinine,

mg/dl

1.0 1.0 1.2 1.1

DREAMSummary of Chlorthalidone / Doxazosin

Comparisons from ALLHAT

Outcome RR (95% CI) p value

CVD 1.20 (1.13 – 1.27) <0.001

Heart failure 1.80 (1.61 – 2.02) <0.001

Stroke 1.26 (1.10 – 1.46) 0.001

CHD 1.03 (0.92 – 1.15) 0.62

All-cause mortality 1.03 (0.94 – 1.13) 0.50

ALLHAT Collab Res Grp. Hypertens 2003; 42:239

Effect of Incident Diabetes on

ALLHAT Endpoints*(Cox Regressions Beginning at 2 Years)

Incident Diabetes / No Diabetes

HR (95% CI)

CHD 1.64 (1.15 – 2.33)

Stroke 1.61 (0.92 – 2.84)

CCVD 1.04 (0.80 – 1.35)

Heart failure 1.37 (0.84 – 2.24)

ESRD 2.86 (0.97 – 8.39)

Total mortality 1.31 (0.95 – 1.81)

* In patients without diabetes at baseline. Adjusted for age, treatment

group, race, gender, smoking, baseline FG, baseline BMI, 2-year BP, 2-

year serum potassium, 2-year atenolol & statin treatment.

ALLHAT

Barzilay J et al: Arch Intern Med. 2006;166:2191

Effect of Change in Fasting

Glucose on ALLHAT Endpoints*(Cox Regressions Beginning at 2 Years)

ΔFG to 2 Yr (per 10 mg/dl) –

HR (95% CI)

CHD 1.02 (0.97 – 1.06)

Stroke 1.00 (0.92 – 1.08)

CCVD 1.00 (0.97 – 1.04)

Heart failure 1.02 (0.96 – 1.08)

ESRD 1.06 (0.94 – 1.19)

Total mortality 1.01 (0.97 – 1.05)

* In patients without diabetes at baseline. Adjusted for

age, treatment group, race, gender, smoking, baseline

FG, baseline BMI, 2-year serum potassium, 2-year

atenolol atenolol & statin treatment.

ALLHAT

Barzilay J et al: Arch Intern Med. 2006;166:2191

Effect of Change in Fasting

Glucose on ALLHAT Endpoints*(Cox Regressions Beginning at 2 Years)

ΔFG to 2 Yr (per 10 mg/dl) –

HR (95% CI)

P compared

with

chlorthalidone

CHD Total 1.02 (0.97 – 1.06) 0.44

Chlorthalidone 1.00 (0.94 – 1.07) 0.94

Amlodipine 0.99 (0.89 – 1.10) 0.87

Lisinopril 1.09 (1.01 – 1.18) 0.03

CCVD Total 1.00 (0.97 – 1.04) 0.84

Chlorthalidone 0.99 (0.94 – 1.03) 0.56

Amlodipine 1.00 (0.94 – 1.07) 0.95

Lisinopril 1.06 (1.00 – 1.12) 0.04

* In patients without diabetes at baseline. Adjusted for age, treatment group, race,

gender, smoking, baseline FG, baseline BMI, 2-year serum potassium, 2-year atenolol

atenolol & statin treatment.

ALLHAT

ALLHATLisinopril/Chlorthalidone

Relative Risk and 95% Confidence

Intervals

6-year Rate per 100

CHD

All-cause Mortality

Stroke

Heart Failure

Combined CVD

ESRD

With Metabolic Syndrome

Favors Lisinopril Favors Chlorthalidone0.50 1 2 3

1.70 (1.13 - 2.54)

1.23 (1.09 - 1.39)

1.49 (1.17 - 1.90)

1.37 (1.06 - 1.76)

1.14 (0.97 - 1.34)

1.17 (0.94 - 1.47)

Without Metabolic Syndrome

Favors Lisinopril Favors Chlorthalidone0.50 1 2

0.75 (0.40 - 1.40)

1.09 (0.94 - 1.27)

1.09 (0.78 - 1.53)

1.31 (0.94 - 1.82)

1.02 (0.86 - 1.23)

1.07 (0.82 - 1.39)

Black Black

Wright et al.

Arch Int Med 2008;

168:207

2010 Consensus Recommendations from the

International Society of Hypertension in Blacks

(ISHIB)

Flack J et al. Hypertens 2010; online

A major recommendation of this consensus

panel was the preference of the

combination of a RAS-inhibitor with a

calcium channel blocker over a RAS-

inhibitor + a diuretic in Black hypertensives

ACCOMPLISH Preliminary Results:Primary* and Secondary End Points

End point Hazard ratio (95% CI)

*Cardiovascular morbidity/mortality 0.80 (0.72–0.90)

Cardiovascular morbidity/mortality (excluding coronary revascularization)

0.79 (0.68–0.92)

Cardiovascular mortality 0.81 (0.62–1.06)

Nonfatal MI 0.81 (0.63–1.05)

Nonfatal stroke 0.87 (0.67–1.13)

Hospitalization for unstable angina 0.74 (0.49–1.11)

Coronary revascularization 0.85 (0.74–0.99)

Resuscitation for sudden death 1.75 (0.73-4.17)

Jamerson KA, et al. NEJM 2008;359:2117

ACCOMPLISH: Design

Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A

*Beta blockers; alpha blockers; clonidine; (loop diuretics).

14 Days Day 1 Month 1 Month 2 Year 5

Screening

Amlodipine 5 mg +benazepril 20 mg

Ra

nd

om

iza

tio

n

Benazepril 40 mg + HCTZ 12.5 mg

Benazepril 40 mg + HCTZ 25 mg

Free add-on antihypertensive agents*

Month 3

Free add-on antihypertensive agents*

Amlodipine 5 mg +benazepril 40 mg

Amlodipine 10 +benazepril 40 mg

Benazepril 20 mg + HCTZ 12.5 mg

Titrated to achieve BP<140/90 mmHg;

<130/80 mmHg in patients with diabetes or

renal insufficiency

Thiazide-type Diuretic Doses in Hypertension Morbidity Trials

Trial Drug Dose of

Thiazide (mg/d)

VA CSP M&M HCTZ 100

HDFP chlorthalidone 25-100

MRC I bendroflumethiazide 10

HAPPHY bendroflumethiazide 5-10

HCTZ 50-100

EWPHE HCTZ/triamterine 25-50

MRC Elderly HCTZ/amiloride 25-50

SHEP chlorthalidone 12.5-25

ALLHAT chlorthalidone 12.5-25

PATS indapamide 2.5

PROGRESS indapamide (+ACEI) 2.5

HYVET indapamide 1.5

ADVANCE BP indapamide (+ACEI) 1.25

Chlorthalidone vs HCTZ Estimated Dosing Equivalence based on Estimated Equivalent BP Reduction

6.5

12

20

28

6.4

18

3.8

24

18

23

0

5

10

15

20

25

30

3 6 12.5 25 50 100 200

HCTZ Chlor.

Re

du

cti

on

in

SB

P (

mm

Hg

)

Carter BL, Ernst ME, Cohen JD. Hypertension 2004;43:4-9.

50 mg HCTZ ~ 25 to 37.5 mg chlorthalidone

Current dosing of 12.5-25 mg can be viewed as compromise between antihypertensive efficacy and kaliuresis

Vd Relative Potency*

Oral Bioavail

Onset (h)

Peak (h)

Half-life (h)

Duration (h)

HCTZ 3-4 L/kg

40% protein bound

1 ~70% 2 4-6 6-9 (single dose)8-15

(long-term

dosing)

12 (single dose)16-24(long-term

dosing)

Chlorthalidone 3-13 L/kg

75% protein bound

98% distribution

into RBC

1 ~65% 2-3 2-6 40(single dose)45-60(long-term

dosing)

24-48(single dose)48-72(long-term

dosing)

Indapamide 20 ~93% 1-2 <2 14 Up to 36

Carter BL, Ernst ME, Cohen JD. Hypertension 2004;43:4-9.

Pharmacokinetics

* per most pharmacology texts; research suggests otherwise

Perspective

• May be promoted by some to encourage use of CCBs over thiazide-type diuretics (each with RAS inhibitors).

• Calls for guidelines changes are premature.

• Dose of thiazide-type diuretic –

– Doses of thiazide-type diuretics equivalent to <25-50 mg/day HCTZ have not been evaluated in clinical outcome trials demonstrating the benefits of HCTZ on CVD outcomes

• In ALLHAT, adequate dosage of diuretic was superior to both the CCB and ACE-inhibitor in preventing HF and unsurpassed for other CVD-renal outcomes, esp in Black patients

8/20/2008

Combination Therapy Needed to Achieve Target SBP Goals

Updated from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

Number of BP meds

Trial/SBP Achieved

1 2 3 4

UKPDS (144 mm Hg)

RENAAL (141 mm Hg)

ALLHAT (135 mm Hg)

IDNT (138 mm Hg)

HOT (138 mm Hg)

INVEST (133 mm Hg)

ABCD (132 mm Hg)

MDRD (132 mm Hg)

AASK (128 mm Hg)

If most hypertensives (especially Black

hypertensives) need 2-3 meds, which

medications would these include

CCB, DIURETICS, RAASI

RAS INHIBITOR USE IN

HYPERTENSIVE BLACKS

• ACEIs/ARBs should be considered first in patients (including Blacks) with nephropathy (esp with proteinuria) and/or heart failure

• Available data suggest that RAS inhibitors are less effective in lowering BP in Black hypertensives in the absence of adequate doses of a diuretic or CCB (and in preventing clinical outcomes)

• ACEI also carry increased of angioedema, esp in Blacks

• In the absence of HF or CKD, particularly in Black hypertensives, beta blockers, ACEIs, and ARBs (and presently renin inhibitors) should be prescribed only in combination with thiazide-type diuretics or calcium channel blockers

The

End

2010 Consensus Recommendations from the

International Society of Hypertension in Blacks

(ISHIB)

Flack J et al. Hypertens 2010; online

POTENTIAL COSTS/RISKS

OF LOWER THAN

INDICATED BP TARGETS

• Increased cost of potentially unnecessary medications

• Increased risk of medication side effects

• Increased clinic visits if BP not at lower goal

• Increased monitoring required

• More complicated regimen that may jeopardize adherence to

evidence-based treatment of other risk factors

• Potential increased risk of lower BP goals

Only Trial Mixed Trial and Cohort Only Cohort

Low BPUsual BP

Cu

mu

lati

ve I

ncid

en

ce (

%)

0

10

20

30

40

50

60

70

Follow-Up Time (Months)

0 12 24 36 48 60 72 84 96 108 120 132

Low BP vs. Usual BP Goal

HR (95%CI) = 0.90 (0.77,1.07)

p = 0.24

TRIAL AND COHORT

ALL PATIENTS

AASK. NEJM 2010;363:10

Only Trial Mixed Trial and Cohort Only Cohort

TRIAL AND COHORT

SUBGROUP WITH UP/Cr > 0.22

Low BPUsual BP

Cu

mu

lati

ve

Inci

den

ce (

%)

0

10

20

30

40

50

60

70

80

90

100

Follow-Up Time (Months)

0 12 24 36 48 60 72 84 96 108 120 132

Low BP vs. Usual BP Goal

HR (95%CI) = 0.72 (0.57,0.92)

p = 0.0076

AASK. NEJM 2010;363:10

Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

Mean # Meds

Intensive: 3.2 3.4 3.5 3.4

Standard: 1.9 2.1 2.2 2.3

ACCORD BP-Lowering: Reduction of SBP to <120 mmHg

significantly Reduces the Rate of STROKE

Intensive Therapy

(n = 2363)

Standard Therapy

(n = 2371)

Outcome Number of

Events

%/Year Number of

Events

%/Year Hazard Ratio(95% CI)

PValue

Primary outcome* 208 1.87 237 2.09 0.88 (0.73-1.06) 0.20

Prespecified secondary outcomes

Nonfatal MI 126 1.13 146 1.28 0.87 (0.68-1.10) 0.25

Any stroke 36 0.32 62 0.53 0.59 (0.39-0.89) 0.01

Nonfatal stroke 34 0.30 55 0.47 0.63 (0.41-0.96) 0.03

Death from any cause 150 1.28 144 1.19 1.07 (0.85-1.35) 0.55

Death from CV cause 60 0.52 58 0.49 1.06 (0.74-1.52) 0.74

Primary outcome plus revascularization

or nonfatal heart disease 521 5.10 551 5.31 0.95 (0.84-1.07) 0.40

Major coronary disease event† 253 2.31 270 2.41 0.94 (0.79-1.12) 0.50

Fatal or nonfatal heart failure 83 0.73 90 0.78 0.94 (0.70-1.26) 0.67

*Primary outcome: composite of nonfatal MI, nonfatal stroke, or death from CV causes

†Major coronary disease events included fatal coronary events, nonfatal MI, and unstable angina

ACCORD: Action to Control Cardiovascular Risk in Diabetes Study

The ACCORD Study Group. N Engl J. Med. 2010;doi: 10.1056/NEJMoa1001286.

Primary Outcome by Pre-defined Subgroups

Also examined DBP tertiles (p=0.70) and number

of screening meds (p=0.44)

The ACCORD Study Group. N Engl J Med 2010;10

SUMMARY AND CONCLUSIONS

• 1/2 - 2/3rd of Black hypertensives are above BP goal of 140/90 mmHg

• The evidence, including that in Black hypertensive patients, does not support BP goals substantially lower than 140/90 mmHg

• The increased cost in medications, clinic visits, monitoring, and potentially increased risk to achieve lower BP goals remains to be justified

• More definitive information should be forthcoming from the SPRINT trial

• In the meantime, efforts to control HTN in Blacks should focus on increasing the number of hypertensives controlled to <140/90 than on getting those already < 140/90 to lower goals

DIFFERENTIATION BETWEEN

MARKETING AND EVIDENCE

―Who are you going to believe -me or the lying data??‖

Dr. Richard Pryor

Chlorthalidone vs HCTZ Estimated Dosing Equivalence based on Estimated Equivalent BP Reduction

6.5

12

20

28

6.4

18

3.8

24

18

23

0

5

10

15

20

25

30

3 6 12.5 25 50 100 200

HCTZ Chlor.

Re

du

cti

on

in

SB

P (

mm

Hg

)

Carter BL, Ernst ME, Cohen JD. Hypertension 2004;43:4-9.

50 mg HCTZ ~ 25 to 37.5 mg chlorthalidone

Current dosing of 12.5-25 mg can be viewed as compromise between antihypertensive efficacy and kaliuresis

Direct and Indirect Comparisons of Chlorthalidone and Nonchlorthalidone

Treatments for 6 Outcomes Based on Placebo-Controlled Trials

RR (95% CI) Indirect

Outcome Chlorthalidone Nonchlorthalidone Comparison,SI (95% Cl)*

Coronary disease 0.74 (0.58-0.95) 0.72 (0.54-0.95) 1.03 (0.71-1.48)

Stroke 0.64 (0.51-0.80) 0.71 (0.60-0.85) 0.90 (0.70-1.17)

Heart failure 0.53 (0.39-0.73) NA NA

CVD events 0.70 (0.61-0.80) 0.76 (0.66-0.87) 0.92 (0.76-1.11)

CVD mortality 0.80 (0.61-1.04) 0.79 (0.65-0.94) 1.01 (0.74-1.39)

Total mortality 0.89 (.0.75-1.06) 0.91 (0.79-1.03) 0.98 (0.79-1.21)

Psaty BM, JAMA 2004; 292:42