Cardiovascular Outcomes in Hypertensives with CHD Randomized

to Amlodipine versus Lisinopril in ALLHAT

Frans Leenen MD, PhD, Chuke Nwachuku MA, MPH, Dr PH, William Cushman MD, Henry Black MD, Lara Simpson MS,

Barry Davis MD, PhD.

For the ALLHAT Collaborative Research Group

Sponsored by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with the Department of Veterans Affairs

U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

ALLHATALLHAT

www.allhat.org

BackgroundBackgroundALLHATALLHAT

* In the 90’s several mainly observational studies reported unfavorable cardiovascular outcomes on therapy with DHP-CCB’s in patients with CHD.

* Placebo-controlled RCT’s such as HOPE or EUROPA (but not PEACE) concluded that (hypertensive) patients with CHD show benefits from ACE-inhibitor therapy beyond that expected from BP lowering per se.

on the other hand:

Objective of Present Post-Hoc AnalysisObjective of Present Post-Hoc Analysis

ALLHATALLHAT

Comparison of cardiovascular and other outcomes among 18,102 patients with or without CHD at baseline randomized to the ACE-inhibitor lisinopril or the DHP-CCB amlodipine.

42,418 high-riskhypertensive patients

90% previously treated10% untreated

STEP 1 AGENTSSTEP 1 AGENTS

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

STEP 2 AND 3 AGENTS (5 years)STEP 2 AND 3 AGENTS (5 years)

Atenolol28.0%

Clonidine10.6%

Reserpine4.3%

Hydralazine10.9%

Hypertension TrialALLHATALLHAT

CHD at BaselineALLHATALLHAT

“known prior MI, angina, primary cardiac

arrest, coronary artery stenosis >50%,

reversible perfusion defect, or major

coronary revascularization procedure”

Baseline Characteristics by CHD at Baseline

CHD at Baseline No CHD at Baseline

Aml(n=2202)

Lis(n=2270)

Aml(n=6777)

Lis(n=6715)

SBP/DBP, mean 145/83 146/83 147/84 147/84

Age in yrs, mean 67.9 68.1 66.6 66.4

On antihypertensive meds (%) 93 92 90 90

Type 2 diabetes (%) 26 27 40 38

Cigarette smoker (%) 15 15 24 24

Female (%) 36 34 51 50

Blacks (%) 24 24 39 39

On aspirin (%) 60 59 29 28

ALLHATALLHAT

74

76

78

80

82

84

86

1.92.0

1.91.7

Y3

1.81.8

1.81.6

Y2 Y4 Y1BLMean # of Meds:

1.71.6

1.51.5

1.71.5

1.51.3

Amlodipine CHD at BLNo CHD at BL

Lisinopril CHD at BLNo CHD at BL

mm

Hg

BP

Δ =1.1

Δ =1.5

Δ =1.0Δ =1.1

132

134

136

138

140

142

144

146

148

Amlodipine - CHD at BL

Amlodipine - No CHD at BL

Lisinopril - CHD at BLLisinopril - No CHD at BL

mm

Hg

BP

Δ =1.5

Δ =0.8

Δ =1.8

Δ =1.2

Baseline and Follow-up BPs by CHD at BLALLHAT

Events – L vs. ARelative Risk and 95% Confidence Intervals

Favors Lisinopril Favors Amlodipine

0.50 1 2

PAD 1.19 (1.01-1.40)

Revascularization 1.00 (0.91-1.11)

Angina 1.09 (1.00-1.19)

HF 0.87 (0.78-0.96)

GI Bleed 1.20 (1.06-1.37)

Cancer 1.01 (0.91-1.12)

ESRD 0.99 (0.77-1.26)

Combined CVD 1.06 (1.00-1.12)

Stroke 1.23 (1.08-1.41)

Combined CHD 1.04 (0.97-1.12)

Death 1.05 (0.97-1.13)

CHD 1.01 (0.91-1.11)

ALLHAT

p=0.047

p=0.045

Cumulative Event Rates for Primary Endpoint by CHD at Baseline and

Treatment GroupALLHAT

0.00

0.05

0.10

0.15

0.20

0 1 2 3 4 5 6 7

Years to Primary Endpoint

AmlodipineLisinopril

No CHD at BL

0.00

0.05

0.10

0.15

0.20

Cu

mu

lati

ve

CH

D R

ate

0 1 2 3 4 5 6 7

Years to Primary Endpoint

AmlodipineLisinopril

CHD at BL

RR (95%CI) P value

L/A 1.15 (0.99-1.32) 0.06

RR (95%CI) P value

L/A 0.99 (0.88-1.13) 0.92

Secondary Endpoints:Lisinopril versus Amlodipine ALLHAT

CHD at BL No CHD at BL

RR (95% CI) P value RR (95% CI) P value

Combined CHD 1.07 (0.96-1.20) 0.24 1.02 (0.93-1.12) 0.64

All-Cause Mortality 1.15 (0.99-1.32) 0.06 1.01 (0.92-1.11) 0.78

ESRD 0.92 (0.54-1.56) 0.75 1.00 (0.76-1.32) 0.99

Cumulative Event Rates for Stroke by CHD at Baseline and Treatment GroupALLHAT

RR (95%CI) P value

L/A 1.31 (1.01-1.69) 0.04

RR (95%CI) P value

L/A 1.20 (1.02-1.41) 0.03

0.00

0.05

0.10

0 1 2 3 4 5 6 7

Years to Stroke

AmlodipineLisinopril

No CHD at BL

Cu

mu

lati

ve

Ss

tro

ke

Ra

te

0.00

0.05

0.10

0 1 2 3 4 5 6 7

Years to Stroke

AmlodipineLisinopril

CHD at BL

Cumulative Event Rates for Heart Failure by CHD at Baseline and

Treatment GroupALLHAT

RR (95%CI) P value

L/A 0.91 (0.76-1.09) 0.31

RR (95%CI) P value

L/A 0.85 (0.74-0.97) 0.02

0.00

0.05

0.10

0.15

0.20

0 1 2 3 4 5 6 7

Years to HF

AmlodipineLisinopril

No CHD at BL

0.00

0.05

0.10

0.15

0.20

Cu

mu

lati

ve

HF

Ra

te

0 1 2 3 4 5 6 7

Years to HF

AmlodipineLisinopril

CHD at BL

Cumulative Event Rates for Angina by CHD at Baseline and

Treatment GroupALLHAT

RR (95%CI) P value

L/A 0.99 (0.87-1.12) 0.87

RR (95%CI) P value

L/A 1.17 (1.03-1.32) 0.02

0.00

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4 5 6 7

Years to Angina

AmlodipineLisinopril

No CHD at BL

0.00

0.05

0.10

0.15

0.20

0.25

Cu

mu

lati

ve

AN

G R

ate

0 1 2 3 4 5 6 7

Years to Angina

AmlodipineLisinopril

CHD at BL

Cumulative Event Rates for PAD by CHD at Baseline and Treatment GroupALLHAT

RR (95%CI) P value

L/A 0.93 (0.71-1.21) 0.58

RR (95%CI) P value

L/A 1.39 (1.12-1.71) 0.002

0.00

0.05

0.10

Cu

mu

lati

ve

PA

D R

ate

0 1 2 3 4 5 6 7

Years to PAD

AmlodipineLisinopril

CHD at BL

0.00

0.05

0.10

0 1 2 3 4 5 6 7

Years to PAD

AmlodipineLisinopril

No CHD at BL

Combined CVD ALLHAT

RR (95%CI) P value

L/A 1.03 (0.94-1.13) 0.54

RR (95%CI) P value

L/A 1.08 (0.99-1.15) 0.06

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

Cu

mu

lati

ve

CC

VD

Ra

te

0 1 2 3 4 5 6 7

Years to CCVD

AmlodipineLisinopril

CHD at BL

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0 1 2 3 4 5 6 7

Years to CCVD

AmlodipineLisinopril

No CHD at BL

SummaryALLHAT

Lisinopril vs. Amlodipine

CHD at baseline No CHD at baseline

CHD, mortality,ESRD

similar similar

Stroke +31% +20%

HFAnginaPAD

-9%-1%-7%

-15%+17% (p=0.07 for interaction)

+39% (p=0.02 for interaction)

Treated SBP level similar + 1-2 mmHg

Combined CVD +3% +8%

ConclusionALLHAT

In hypertensive patients with CHD, lisinopril and amlodipine – based treatment provides equivalent BP control and equivalent rates for most outcomes.

Patients with and without CHD have similar higher stroke rates and lower HF rates on lisinopril versus amlodipine.

This post-hoc analysis provides no evidence for specific benefits by ACE-inhibitor based treatment in patients with CHD.

Events for CHD by RaceRelative Risk and 95% Confidence Intervals

Revascularization

Combined CVD

Combined CHD

Non-Blacks

Favors Lisinopril Favors Amlodipine

0.50 1 2

PAD 0.98 (0.72-1.33)

1.00 (0.84-1.19)

Angina 0.99 (0.86-1.14)

HF 0.90 (0.73-1.11)

GI Bleed 1.00 (0.77-1.30)

Cancer 1.03 (0.82-1.31)

ESRD 0.65 (0.33-1.29)

1.03 (0.93-1.15)

Stroke 1.20 (0.89-1.62)

1.07 (0.95-1.22)

Death 1.15 (0.97-1.36)

CHD 1.08 (0.90-1.30)

Blacks

Favors Lisinopril Favors Amlodipine

0.50 1 2

0.76 (0.43-1.35)

1.17 (0.79-1.73)

0.98 (0.73-1.33)

0.95 (0.66-1.35)

1.20 (0.78-1.86)

0.92 (0.61-1.40)

1.72 (0.68-4.38)

1.02 (0.84-1.24)

1.63 (1.01-2.64)

1.06 (0.82-1.37)

1.14 (0.87-1.49)

0.95 (0.68-1.35)

ALLHAT

Non-Blacks

Favors Lisinopril Favors Amlodipine

0.50 1 2

PAD 1.35 (1.04-1.77)

Revascularization 0.95 (0.82-1.12)

Angina 1.12 (0.96-1.31)

HF 0.83 (0.69-0.99)

GI Bleed 1.27 (1.03-1.55)

Cancer 0.95 (0.81-1.11)

ESRD 0.97 (0.63-1.49)

Combined CVD 1.02 (0.93-1.12)

Stroke 1.00 (0.79-1.25)

Combined CHD 0.97 (0.86-1.09)

Death 0.96 (0.85-1.09)

CHD 0.91 (0.78-1.06)

Blacks

Favors Lisinopril Favors Amlodipine

0.50 1 2

1.44 (1.03-2.02)

1.08 (0.81-1.45)

1.24 (1.01-1.52)

0.87 (0.71-1.08)

1.30 (1.03-1.64)

1.10 (0.90-1.34)

1.03 (0.71-1.48)

1.16 (1.03-1.30)

1.48 (1.17-1.88)

1.14 (0.97-1.33)

1.08 (0.94-1.25)

1.17 (0.95-1.43)

Events for No CHD by RaceRelative Risk and 95% Confidence IntervalsALLHAT

ALLHAT Events for Non-Blacks by CHD StatusRelative Risk and 95% Confidence Intervals

No CHD at Baseline

Favors Lisinopril Favors Amlodipine

0.50 1 2

1.35 (1.04-1.77)

0.95 (0.82-1.12)

1.12 (0.96-1.31)

0.83 (0.69-0.99)

1.27 (1.03-1.55)

0.95 (0.81-1.11)

0.97 (0.63-1.49)

1.02 (0.93-1.12)

1.00 (0.79-1.25)

0.97 (0.86-1.09)

0.96 (0.85-1.09)

0.91 (0.78-1.06)

CHD at Baseline

Favors Lisinopril Favors Amlodipine

0.50 1 2

PAD 0.98 (0.72-1.33)

1.00 (0.84-1.19)

Angina 0.99 (0.86-1.14)

HF 0.90 (0.73-1.11)

GI Bleed 1.00 (0.77-1.30)

Cancer 1.03 (0.82-1.31)

ESRD 0.65 (0.33-1.29)

1.03 (0.93-1.15)

Stroke 1.20 (0.89-1.62)

1.07 (0.95-1.22)

Death 1.15 (0.97-1.36)

CHD 1.08 (0.90-1.30)

Revascularization

Combined CVD

Combined CHD

ALLHATEvents for Blacks by CHD Status

Relative Risk and 95% Confidence Intervals

PAD

Revascularization

Angina

HF

GI Bleed

Cancer

ESRD

Combined CVD

Stroke

Combined CHD

Death

CHD

CHD at Baseline

Favors Lisinopril Favors Amlodipine

0.50 1 2

0.76 (0.43-1.35)

1.17 (0.79-1.73)

0.98 (0.73-1.33)

0.95 (0.66-1.35)

1.20 (0.78-1.86)

0.92 (0.61-1.40)

1.72 (0.68-4.38)

1.02 (0.84-1.24)

1.63 (1.01-2.64)

1.06 (0.82-1.37)

1.14 (0.87-1.49)

0.95 (0.68-1.35)

No CHD at Baseline

Favors Lisinopril Favors Amlodipine

0.50 1 2

1.44 (1.03-2.02)

1.08 (0.81-1.45)

1.24 (1.01-1.52)

0.87 (0.71-1.08)

1.30 (1.03-1.64)

1.10 (0.90-1.34)

1.03 (0.71-1.48)

1.16 (1.03-1.30)

1.48 (1.17-1.88)

1.14 (0.97-1.33)

1.08 (0.94-1.25)

1.17 (0.95-1.43)

Outcomes L vs. A:RR and 95% Confidence Intervals

CHD at Baseline

Favors Lisinopril Favors Amlodipine

0.50 1 2

PAD 0.93 (0.71-1.21)

Revascularization 1.03 (0.88-1.20)

Angina 0.99 (0.87-1.12)

HF 0.91 (0.76-1.09)

GI Bleed 1.05 (0.84-1.32)

Cancer 1.01 (0.82-1.24)

ESRD 0.92 (0.54-1.56)

Combined CVD 1.03 (0.94-1.13)

Stroke 1.31 (1.01-1.69)

Combined CHD 1.07 (0.96-1.20)

Death 1.15 (0.99-1.32)

CHD 1.05 (0.89-1.24)

No CHD at Baseline

Favors Lisinopril Favors Amlodipine

0.50 1 2

1.39 (1.12-1.71)

0.98 (0.86-1.13)

1.17 (1.03-1.32)

0.85 (0.74-0.97)

1.28 (1.10-1.50)

1.01 (0.89-1.14)

1.00 (0.76-1.32)

1.07 (0.99-1.15)

1.20 (1.02-1.41)

1.02 (0.93-1.12)

1.01 (0.92-1.11)

0.99 (0.88-1.13)

ALLHAT

Outcomes A vs. C:RR and 95% Confidence Intervals

No CHD at Baseline

Favors Amlodipine Favors Chlorthalidone0.50 1 2

0.79 (0.66-0.96)

1.08 (0.96-1.23)

0.99 (0.88-1.11)

1.48 (1.30-1.68)

0.88 (0.76-1.02)

1.06 (0.95-1.18)

1.23 (0.95-1.60)

1.05 (0.98-1.12)

0.96 (0.82-1.11)

1.02 (0.93-1.11)

0.99 (0.91-1.08)

1.01 (0.90-1.13)

CHD at Baseline

Favors Amlodipine Favors Chlorthalidone0.50 1 2

PAD 1.04 (0.82-1.31)

Revascularization 1.16 (1.00-1.33)

Angina 1.10 (0.98-1.24)

HF 1.29 (1.09-1.52)

GI Bleed 1.00 (0.82-1.23)

Cancer 0.92 (0.77-1.10)

ESRD 0.88 (0.56-1.38)

Combined CVD 1.07 (0.98-1.16)

Stroke 0.90 (0.71-1.13)

Combined CHD 1.02 (0.92-1.13)

Death 0.89 (0.79-1.01)

CHD 0.95 (0.82-1.10)

ALLHAT

Outcomes A vs. C in Blacks:RR and 95% Confidence Intervals

CHD at Baseline in Blacks

Favors Amlodipine Favors Chlorthalidone

0.50 1 2

PAD 1.18 (0.73-1.91)

Revascularization 1.37 (0.94-1.99)

Angina 1.08 (0.83-1.41)

HF 1.47 (1.06-2.04)

GI Bleed 0.94 (0.63-1.39)

Cancer 1.07 (0.75-1.55)

ESRD0.70 (0.29-1.68)

Combined CVD 1.16 (0.97-1.38)

Stroke 0.89 (0.56-1.42)

Combined CHD 1.19 (0.94-1.50)

Death 0.96 (0.76-1.23)

CHD 1.19 (0.87-1.61)

No CHD at Baseline in Blacks

Favors Amlodipine Favors Chlorthalidone

0.50 1 2

0.77 (0.56-1.05)

0.97 (0.75-1.27)

1.10 (0.91-1.35)

1.53 (1.26-1.88)

1.01 (0.81-1.26)

0.95 (0.79-1.14)

1.27 (0.90-1.80)

1.05 (0.94-1.16)

0.96 (0.76-1.21)

1.00 (0.87-1.16)

0.99 (0.87-1.13)

0.95 (0.79-1.15)

ALLHAT

Outcomes A vs. C in Non-Blacks:RR and 95% Confidence Intervals

CHD at Baseline in Non-Blacks

Favors Amlodipine Favors Chlorthalidone

0.50 1 2

PAD 1.00 (0.76-1.31)

Revascularization 1.12 (0.96-1.30)

Angina 1.11 (0.97-1.26)

HF 1.24 (1.03-1.49)

GI Bleed 1.03 (0.81-1.30)

Cancer 0.87 (0.71-1.08)

ESRD 1.96 (0.56-1.62)

Combined CVD 1.04 (0.95-1.14)

Stroke 0.90(0.69-1.18)

Combined CHD 0.98 (0.87-1.10)

Death 0.87 (0.75-1.01)

CHD 0.89 (0.76-1.05)

No CHD at Baseline in Non-Blacks

Favors Amlodipine Favors Chlorthalidone

0.50 1 2

0.81 (0.64-1.04)

1.12 (0.97-1.29)

0.94 (0.82-1.08)

1.44 (1.23-1.70)

0.80 (0.67-0.97)

1.13 (0.98-1.30)

1.18 (0.79-1.74)

1.05 (0.97-1.14)

0.95 (0.78-1.16)

1.02 (0.92-1.17)

0.99 (0.89-1.11)

1.04 (0.91-1.10)

ALLHAT

Outcomes L vs. C:RR and 95% Confidence Intervals

No CHD at Baseline

Favors Lisinopril Favors Chlorthalidone0.50 1 2

1.10 (0.92-1.31)

1.06 (0.94-1.21)

1.16 (1.04-1.29)

1.25 (1.09-1.43)

1.13 (1.00-1.29)

1.06 (0.95-1.19)

1.23 (0.95-1.60)

1.12 (1.05-1.20)

1.15 (1.00-1.32)

1.04 (0.96-1.13)

1.01 (0.93-1.09)

1.00 (0.90-1.12)

CHD at Baseline

Favors Lisinopril Favors Chlorthalidone0.50 1 2

PAD 0.96 (0.76-1.22)

Revascularization 1.18 (1.03-1.36)

Angina 1.09 (0.97-1.22)

HF 1.18 (1.00-1.39)

GI Bleed 1.06 (0.87-1.29)

Cancer 0.93 (0.77-1.11)

ESRD 0.80 (0.51-1.28)

Combined CVD 1.10 (1.01-1.19)

Stroke 1.17 (0.95-1.45)

Combined CHD 1.09 (0.99-1.21)

Death 1.02 (0.91-1.15)

CHD 1.00 (0.87-1.15)

ALLHAT

Outcomes L vs. C in Blacks:RR and 95% Confidence Intervals

CHD at Baseline in Blacks

Favors Lisinopril Favors Chlorthalidone

0.50 1 2

PAD 0.90 (0.54-1.53)

Revascularization 1.59(1.11-2.28)

Angina 1.06 (0.81-1.38)

HF 1.39 (0.99-1.94)

GI Bleed 1.13 (0.78-1.64

Cancer 1.00 (0.69-1.45)

ESRD 1.21 (0.58-2.52)

Combined CVD 1.18 (0.99-1.40)

Stroke 1.45 (0.98-2.16)

Combined CHD 1.26 (1.01-1.59)

Death 1.10 (0.88-1.39)

CHD 1.14 (0.83-1.55)

No CHD at Baseline in Blacks

Favors Lisinopril Favors Chlorthalidone

0.50 1 2

1.11 (0.84-1.47)

1.05 (0.81-1.36)

1.37 (1.14-1.65)

1.34 (1.09-1.65)

1.32 (1.07-1.62)

1.04 (0.88-1.24)

1.30 (0.92-1.83)

1.22 (1.10-1.35)

1.43 (1.16-1.76)

1.14 (0.99-1.32)

1.07 (0.95-1.22)

1.11 (0.93-1.33)

ALLHAT

Outcomes L vs. C in Non-Blacks:RR and 95% Confidence Intervals

No CHD at Baseline in Non-Blacks

Favors Lisinopril Favors Chlorthalidone

0.50 1 2

1.10 (0.88-1.37)

1.07 (0.93-1.24)

1.06 (0.92-1.21)

1.19 (1.00-1.42)

1.02 (0.85-1.21)

1.08 (0.93-1.24)

1.15 (0.77-1.71)

1.07 (0.99-1.16)

0.95 (0.77-1.16)

0.99 (0.89-1.10)

0.96 (0.86-1.07)

0.94 (0.82-1.09)

CHD at Baseline in Non-Blacks

Favors Lisinopril Favors Chlorthalidone

0.50 1 2

PAD 0.98 (0.75-1.28)

Revascularization 1.12 (0.96-1.30)

Angina 1.10 (0.96-1.24)

HF 1.12 (0.92-1.35)

GI Bleed 1.03 (0.82-1.30)

Cancer 0.91 (0.74-1.11)

ESRD 0.63 (0.34-1.16)

Combined CVD 1.08 (0.98-1.18)

Stroke 1.08 (0.83-1.39)

Combined CHD 1.05 (0.94-1.17)

Death 1.00 (0.86-1.15)

CHD 0.97(0.83-1.13)

ALLHAT