disclosure of relationships for william c. cushman, md, over the past 12 months

Is It the Achieved Blood Pressure or Specific Medications

that Make a Difference in Outcome,

or Is the Question Moot?William C. Cushman, MD

Professor, Preventive Medicine and MedicineUniversity of Tennessee College of Medicine

Chief, Preventive MedicineVA Medical Center, Memphis, Tennessee

3

DISCLOSURE OF RELATIONSHIPS for William C. Cushman, MD, Over the Past 12

Months Type of RelationshipType of Relationship Name of CompanyName of Company

Grant/Research SupportGrant/Research Support Astra-Zeneca, Abbott, Novartis,Astra-Zeneca, Abbott, Novartis,Aventis, King PharmaceuticalsAventis, King Pharmaceuticals

ConsultantConsultant Sanofi-Aventis, Bristol-Myers Squibb, Sanofi-Aventis, Bristol-Myers Squibb, Novartis, Pfizer, Sankyo, Forest, Novartis, Pfizer, Sankyo, Forest, MyogenMyogen

Speakers BureauSpeakers Bureau nonenone

Major Stock ShareholderMajor Stock Shareholder nonenone

Other Support, Other Support, Tangible or IntangibleTangible or Intangible

nonenone

VA Cooperative Morbidity Trial VA Cooperative Morbidity Trial in Hypertensionin Hypertension

39

55

1.4

18

0

15

30

45

60

75

115-129 90-114

Entry Diastolic BP, mm Hg

CV

Ev

en

ts (

%)

Placebo Active

Stopped afterStopped after1.5 years1.5 years

Stopped afterStopped after3.3 yrs3.3 yrs

96% RR96% RR

67% RR67% RR

Blood pressure (BP) goal: DBP <90 mm Hg.Blood pressure (BP) goal: DBP <90 mm Hg.

Therapy: HCTZ + reserpine + hydralazine.Therapy: HCTZ + reserpine + hydralazine.

NNT = 2.7 for both.NNT = 2.7 for both.

RR = risk reduction.RR = risk reduction.

JAMA.JAMA. 1967;202(11):1028-1034. 1967;202(11):1028-1034.

JAMA.JAMA. 1970;213(7): 1143-1152. 1970;213(7): 1143-1152.

(N = 143) (N = 380)

Blood Pressure Levels* and Event Blood Pressure Levels* and Event Reduction Reduction

in Selected Clinical Trialsin Selected Clinical TrialsTrialTrial Baseline BPBaseline BP Treated BPTreated BP Event Event ↓↓

ActiveActive ControlControl

HDFPHDFP 159/101 159/101 131/86131/86 142/91142/91 17% - mortality17% - mortality

SHEPSHEP 170/77170/77 144/68144/68 155/73155/73 36% - stroke36% - stroke

Syst-EURSyst-EUR 174/86174/86 151/79151/79 161/84161/84 42% - stroke42% - stroke

PROGRESSPROGRESS 147/86147/86 134/78134/78 143/82143/82 28% - stroke28% - stroke

PROGRESS - HTNPROGRESS - HTN 159/93159/93 138/81138/81 146/84146/84 32% - stroke32% - stroke

HOPEHOPE 139/79139/79 135/76135/76 138/78138/78 22% - 22% - CVDCVD

* mm HgHypertension Detection and Follow-up Program (HDFP). JAMA. 1979;242(23):2562-2571. Systolic

Hypertension in the Elderly Program (SHEP) Cooperative Research Group. JAMA. 1991;265(24):3255-3264. Systolic Hypertension in Europe Trial (Syst-EUR) Investigators. Lancet. 1997;350:757-764.

Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Collaborative Group. Lancet. 2001;358(9287):1033-1041. Heart Outcomes Prevention Valuation Study (HOPE) Investigators. N Engl J

Med. 2000;342:145-153.

Low-dose Diuretics versus PlaceboLow-dose Diuretics versus Placebo

CHDCHD 0.790.79 0.69-0.920.69-0.92 0.0020.002

Heart failureHeart failure 0.510.51 0.42-0.620.42-0.62 <0.001<0.001

StrokeStroke 0.710.71 0.63-0.810.63-0.81 <0.001<0.001

CVD eventsCVD events 0.760.76 0.69-0.830.69-0.83 <0.001<0.001

CVD mortalityCVD mortality 0.810.81 0.73-0.920.73-0.92 0.0010.001

Total mortalityTotal mortality 0.900.90 0.84-0.960.84-0.96 0.0020.002

OutcomeOutcome RRRR 95% CI95% CI PP

0.400.40 0.650.65 0.900.90 1.151.15 1.401.40

Low-dose diuretics better Low-dose diuretics worseLow-dose diuretics better Low-dose diuretics worse

Network Meta-analysis Network Meta-analysis of Antihypertensive Drugsof Antihypertensive Drugs

Psaty BM et al. JAMA. 2003;289:2534-2544.

Systolic blood pressure difference between randomised groups (mmHg).

Rel

ativ

e ri

sk o

f st

roke

Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.

Rel

ativ

e ri

sk o

f C

VD

0.25

0.50

0.75

1.00

1.25

1.50

Rel

ativ

e ri

sk o

f h

ear t

fa

ilure

0.25

0.50

0.75

1.00

1.25

1.50

-10 -8 -6 -4 -2 0 2 4

BP Reduction and Major Cardiovascular BP Reduction and Major Cardiovascular OutcomesOutcomes

-10 -8 -6 -4 -2 0 2 4

Rel

ativ

e ri

sk o

f C

HD

StrokeStroke

CHDCHDHeart FailureHeart Failure

CVDCVD

MRC in the Elderly:MRC in the Elderly:Mean Level of BP by Sex and Mean Level of BP by Sex and

TreatmentTreatment

140

150

160

170

180

190

140

150

160

170

180

190

70

75

80

85

90

95

70

75

80

85

90

95

Mea

n sy

stol

ic B

PM

ean

dias

tolic

BP

Men Women

Placebo-blockerDiuretic

MRC Working Party. BMJ. 1992;304:405-412.

Interval from entry (months)Interval from entry (months)

MRC in the Elderly: MRC in the Elderly: Effects of Treatment on Stroke Effects of Treatment on Stroke

IncidenceIncidence

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7

Cu

mu

lati

ve %

eve

nts

Interval from entry (years)

Treatment vs Placebo, Treatment vs Placebo, PP = 0.04 (RR = 25%) = 0.04 (RR = 25%)

N = 4396 N = 4396


Diuretic vs Diuretic vs ββ-blocker,-blocker,PP = 0.33 = 0.33


MRC in the Elderly: MRC in the Elderly: Effects of Treatment on Coronary Effects of Treatment on Coronary

EventsEvents

0

2

4

6

8

10

0 1 2 3 4 5 6 7

Cu

mu

lati

ve %

eve

nts

Interval from entry (years)

Treatment vs Placebo, Treatment vs Placebo, PP = 0.08 (RR = 19%) = 0.08 (RR = 19%)


N = 4396 N = 4396



25.2 24.6

17.4

0

5

10

15

20

25

30

Placebo Atenolol HCTZ/amiloride

Randomized Group

CV

D E

ve

nts

/1,0

00

pt-

yrs

MRC in the Elderly: Effects of MRC in the Elderly: Effects of Treatment on Cardiovascular EventsTreatment on Cardiovascular Events


N = 4396 N = 4396


12

90% previously treated10% untreated

42,418 high-riskhypertensive patients

Chlorthalidone12.5-25 mg

Amlodipine2.5-10 mg

Lisinopril10-40 mg

Doxazosin1-8 mg

N=15,255 N=9,048 N=9,054 N=9,061

Atenolol28.0%

Clonidine10.6%

Reserpine4.3%

Hydralazine10.9%

Hypertension TrialHypertension TrialALLHAT

STEP 2 AND 3 AGENTSSTEP 2 AND 3 AGENTS

STEP 1 AGENTS (Double-blind)STEP 1 AGENTS (Double-blind)

13

ALLHAT: Doxazosin vs ALLHAT: Doxazosin vs ChlorthalidoneChlorthalidone

SBP Results by Treatment GroupSBP Results by Treatment Group

130

135

140

145

150

0 6 12 18 24 30 36 42 48

Months

mm

Hg

Chlorthalidone Doxazosin

There were no There were no differences in DBP.differences in DBP.

ALLHAT Collaborative Research group. JAMA. 2000;283:1967-1975

BLBL 6M6M 1Y1Y 2Y2Y 4Y4Y

DOXDOX 146.3146.3 141.1141.1 140.1140.1 138.2138.2 137.4137.4

CTDCTD 146.2146.2 138.2138.2 136.9136.9 135.9135.9 135.3135.3

1414

Relative Risk and 95% Confidence IntervalsRelative Risk and 95% Confidence Intervals

Final Outcomes Final Outcomes ResultsResults

Doxazosin vs. Chlorthalidone

Favors Doxazosin Favors ChlorthalidoneFavors Doxazosin Favors Chlorthalidone0.500.50 11 22 33

CHD

All-Cause Mortality

Combined CHD

Stroke, p=0.001

Heart Failure, p<0.001

Combined CVD, p<0.001 1.20 (1.13 - 1.27)

1.80 (1.61 - 2.02)

1.26 (1.10 - 1.46)

1.07 (0.99 - 1.16)

1.03 (0.94 - 1.13)

1.03 (0.92 - 1.15)

ALLHAT Collaborative Research group. Hypertension. 2003;42:239-246.

ALLHATALLHAT

15

Estimated BP Effect on RR Estimated BP Effect on RR DifferencesDifferences

• A 3 mm Hg higher SBP in the doxazosin group could explain a 10% to 20% difference in HF* but not an 80% difference in risk.

• 3 mm Hg could account for 15-20% increase in stroke risk**—26% was observed.

• Thus, the observed BP differential may explain much of the stroke, but not HF, differences observed between chlorthalidone and doxazosin in ALLHAT.

* Based on SHEP and Syst-EUR.** Based on meta-analysis of all diuretic/-blocker trials.

ALLHAT Collaborative Research group. JAMA. 2000; 283:1967-1975; Hypertension. 2003;42:239-246.

16

Doxazosin vs Doxazosin vs Chlorthalidone:Chlorthalidone:

Heart Failure, Adjusting* for BPALLHAT

ALL HFALL HF

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

Hosp./Fatal HFHosp./Fatal HF

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

As randomizedAs randomized2.042.04††

(1.79, 2.32)(1.79, 2.32)

1.831.83††

(1.58, 2.13)(1.58, 2.13)

AdjustedAdjusted2.002.00††

(1.72, 2.32)(1.72, 2.32)

1.801.80††

(1.51, 2.13)(1.51, 2.13)

*Adjusted for BL SBP/DBP and FU SBP/DBP

Davis BR et al. Ann Intern Med. 2002;137:313-320.

†† PP < 0.001 < 0.001

17

0

0.5

1

1.5

2

140/90 mm Hg <140/90 mm Hg

Rat

e /1

00p

t-yr

s

Chlorthalidone Doxazosin

Doxazosin vs Chlorthalidone:Doxazosin vs Chlorthalidone:Heart Failure Beyond 1 Yr Heart Failure Beyond 1 Yr

by BP Level at 1 Yrby BP Level at 1 Yr

RR=1.17RR=1.17RR=1.63*RR=1.63*

Davis BR et al. Ann Intern Med. 2002;137:313-320.

RR = hazard ratio (doxazosin/chlorthalidone)RR = hazard ratio (doxazosin/chlorthalidone)*CI = 1.20-2.05*CI = 1.20-2.05

≥≥

18 BP Levels by Treatment Group BP Levels by Treatment Group for Chlorthalidone, Amlodipine, and for Chlorthalidone, Amlodipine, and

LisinoprilLisinopril

BP <140/90 mm Hg at 5 yrs: Chlorthalidone 68% Amlodipine 66% Lisinopril 61%

ALLHAT Collaborative Research group JAMA. 2002;288:2981-2997.

~2 mm Hg lower in2 mm Hg lower inchlorthalidone vs chlorthalidone vs lisinopril grouplisinopril group

~1 mm Hg lower in amlodipine group

19

Major OutcomesMajor OutcomesRelative Risks and 95% Confidence Intervals

Amlodipine/Chlorthalidone

0.50 1 2

ESRD 1.12 (0.89-1.40)

Heart Failure 1.38 (1.25-1.52)

Combined CVD 1.04 (0.99-1.09)

Stroke 0.93 (0.82-1.06)

All-Cause Mortality 0.96 (0.89-1.02)

CHD 0.98 (0.90-1.07)

Favors FavorsAmlodipine Chlorthalidone

Lisinopril/ChlorthalidoneLisinopril/Chlorthalidone

0.500.50 11 22

1.11 (0.88-1.38)1.11 (0.88-1.38)

1.19 (1.07-1.31)1.19 (1.07-1.31)

1.10 (1.05-1.16)1.10 (1.05-1.16)

1.15 (1.02-1.30)1.15 (1.02-1.30)

1.00 (0.94-1.08)1.00 (0.94-1.08)

0.99 (0.91-1.08)0.99 (0.91-1.08)

Favors FavorsLisinopril Chlorthalidone

ALLHAT

ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.

1.29 (0.94 - 1.75)1.29 (0.94 - 1.75)ESRDESRD

1.32 (1.11 - 1.58)1.32 (1.11 - 1.58)Heart FailureHeart Failure

1.40 (1.17 - 1.68)1.40 (1.17 - 1.68)Stroke*Stroke*

1.19 (1.09 - 1.30)1.19 (1.09 - 1.30)Combined CVD*Combined CVD*

1.06 (0.95 - 1.18)1.06 (0.95 - 1.18)All-Cause MortalityAll-Cause Mortality

1.10 (0.94 - 1.28)1.10 (0.94 - 1.28)CHDCHD

Favors FavorsFavors FavorsLisinopril ChlorthalidoneLisinopril Chlorthalidone

0.500.50 11 22

0.93 (0.67 - 1.30)0.93 (0.67 - 1.30)

1.15 (1.01 - 1.30)1.15 (1.01 - 1.30)

1.00 (0.85 - 1.17)1.00 (0.85 - 1.17)

1.06 (1.00 - 1.13)1.06 (1.00 - 1.13)

0.97 (0.89 - 1.06)0.97 (0.89 - 1.06)

0.94 (0.85 - 1.05)0.94 (0.85 - 1.05)

0.50 1 2 0.50 1 2

Only Subgroup Differences:Only Subgroup Differences:Lisinopril vs Chlorthalidone in Lisinopril vs Chlorthalidone in Blacks/Non-Blacks for CVD & Blacks/Non-Blacks for CVD &

Stroke Stroke BlacksBlacks Non-BlacksNon-Blacks

ALLHATALLHAT

Favors FavorsFavors FavorsLisinopril ChlorthalidoneLisinopril Chlorthalidone

Wright JT et al. JAMA. 2005; 293: 1595-1608. * Significant interaction* Significant interaction

21

Cumulative Event Rates for Heart Cumulative Event Rates for Heart Failure Failure by ALLHAT Treatment Group for by ALLHAT Treatment Group for Year 1Year 1

ALLHATALLHAT

Cu

mu

lati

ve H

F R

ate

Cu

mu

lati

ve H

F R

ate

Years to HFYears to HF

00 .5.5 1100

.01.01

..0202

ChlorthalidoneChlorthalidone

AmlodipineAmlodipine

LisinoprilLisinopril

RR (95% CI)RR (95% CI) PP value value

A/CA/C 2.32 (1.83-2.94)2.32 (1.83-2.94) <.001<.001

L/CL/C 2.22 (1.75-2.82)2.22 (1.75-2.82) <.001<.001

Davis, et al. Circulation. 2006;113:2201-2210.

22

0

2

4

6

8

Chlorthalidone Amlodipine Lisinopril

5 Y

r E

ven

t R

ate/

100

140/90 mm Hg <140/90 mm Hg

Heart Failure Beyond 1 Yr by BP Level at 1 Heart Failure Beyond 1 Yr by BP Level at 1 Yr in Chlorthalidone, Amlodipine and Yr in Chlorthalidone, Amlodipine and

Lisinopril GroupsLisinopril Groups

RR U/C RR U/C = 1.41*= 1.41*

ALLHAT. Unpublished data. 2006.

≥≥

RR U/C = hazard ratio uncontrolled/controlledRR U/C = hazard ratio uncontrolled/controlled*p<0.001, **p=0.017, *p<0.001, **p=0.017, ††p=0.023p=0.023

RR U/CRR U/C= 1.29= 1.29††

RR U/C RR U/C = 1.27**= 1.27**

23

0

2

4

6

8

140/90 mm Hg <140/90 mm Hg

5 Y

r E

ven

t R

ate/

100

Chlorthalidone Amlodipine Lisinopril

Amlodipine and Lisinopril vs Amlodipine and Lisinopril vs Chlorthalidone:Chlorthalidone:

Heart Failure Beyond 1 Yr by BP Level at Heart Failure Beyond 1 Yr by BP Level at 1 Yr1 Yr

RR A/C RR A/C = 1.16= 1.16

RR A/CRR A/C= 1.30*= 1.30*

ALLHAT. Unpublished data. 2006.

≥≥

RR = hazard ratioRR = hazard ratio *p<0.01*p<0.01

RR L/CRR L/C= 0.92= 0.92

RR L/CRR L/C= 1.01= 1.01

24 BP Differences: BP Differences: Lisinopril versus Lisinopril versus ChlorthalidoneChlorthalidone

Mean follow-up SBP for L versus CMean follow-up SBP for L versus C 2 mm Hg higher2 mm Hg higher——all participantsall participants 4 mm Hg higher4 mm Hg higher——Black participantsBlack participants

Adjustment for follow-up SBP/DBP as time-Adjustment for follow-up SBP/DBP as time-dependent covariates in a Cox regression model dependent covariates in a Cox regression model slightly reduced the relative risks, but they slightly reduced the relative risks, but they remained statistically significant.remained statistically significant. Stroke (1.15 Stroke (1.15 →→ 1.12) & HF (1.20 1.12) & HF (1.20 →→ 1.17), overall 1.17), overall Stroke (1.40 Stroke (1.40 →→ 1.35) & HF (1.32 1.35) & HF (1.32 →→ 1.26), for 1.26), for

BlacksBlacks

ALLHAT


25

Prospective observational studies predict that 2 Prospective observational studies predict that 2 mm Hg difference mm Hg difference →→ 9% higher stroke mortality 9% higher stroke mortality and 6% higher HF mortality, versus 15 and 19% and 6% higher HF mortality, versus 15 and 19% higher risk (fatal + nonfatal events) observed in higher risk (fatal + nonfatal events) observed in ALLHAT.ALLHAT.

Based on same data, 4 mm Hg difference in Based on same data, 4 mm Hg difference in blacks would predict 19% higher stroke mortality blacks would predict 19% higher stroke mortality and 14% higher HF mortality, versus 40% and and 14% higher HF mortality, versus 40% and 32% higher risk (fatal + nonfatal events) 32% higher risk (fatal + nonfatal events) observed in ALLHAT.observed in ALLHAT.

BP Differences: BP Differences: Lisinopril versus Lisinopril versus ChlorthalidoneChlorthalidone

(continued)(continued)

ALLHAT


26

0.5 0.5 1.0 1.0 2.02.0

Cardiovascular Events and Total Cardiovascular Events and Total Mortality in SCOPE and LIFEMortality in SCOPE and LIFE

Lithel H et al.Lithel H et al. J Hypertens J Hypertens. 2003;21:875–886.. 2003;21:875–886.

Relative riskRelative risk

Major CV event Major CV event SCOPESCOPELIFELIFE

CV death CV death SCOPESCOPELIFELIFE

Fatal/non-fatal stroke Fatal/non-fatal stroke SCOPESCOPELIFELIFE

Fatal/non-fatal MI Fatal/non-fatal MI SCOPESCOPELIFELIFE

Total Mortality Total Mortality SCOPESCOPELIFELIFE

Favors ATFavors AT11 blockade blockade Favors controlFavors control

There was little BP There was little BP difference in LIFE and difference in LIFE and 3.2/1.6 mm Hg lower BP 3.2/1.6 mm Hg lower BP in the candesartan in the candesartan group in SCOPE, but group in SCOPE, but event RRs were similarevent RRs were similar

LIFE (n=9193): losartan vs atenololLIFE (n=9193): losartan vs atenololSCOPE (n=4964): candesartan vs placeboSCOPE (n=4964): candesartan vs placebo

2727

Initial Combinations of Initial Combinations of Medications Medications

for Management of Hypertension*for Management of Hypertension*

Initial Combinations of Initial Combinations of Medications Medications

for Management of Hypertension*for Management of Hypertension*DiureticsDiuretics

ACE inhibitorsACE inhibitorsoror

ARBsARBs

CalciumCalciumantagonistsantagonists

* Compelling indications may modify this.

Achieved Blood Pressure Achieved Blood Pressure Versus Specific Medications: Effects on Versus Specific Medications: Effects on

OutcomesOutcomes


OutcomesOutcomes

Drugs with very different physiologic effects may

logically have different effects on organs/events

independent of BP.

In ALLHAT and other trials, adjustment of clinical

event rates based on observational analyses of BP

differences are limited by variability of BP

measurement and absence of non-clinic BPs.

Outcome differences in many studies are not fully

explained by clinically detectable BP differences.

BP control IS of paramount importance, but it

DOES also matter which drugs we use.


OutcomesOutcomes(continued)(continued)


OutcomesOutcomes(continued)(continued)

disclosure of relationships for william c. cushman, md, over the past 12 months

Documents

stroke risk

effects of treatment

doxazosin group

relative risk of cvd0

bp reduction

achieved blood pressure

treatment groupthere

systolic hypertension