Results of Monotherapy in ALLHAT: On-treatment

Analyses

ALLHAT

Outcomes for participants who received no step-up drugs

Objective and Rationale

• To compare major outcomes for pts remaining on blinded monotherapy.

• Aim: to remove effects of step-up drugs that may have differed in effectiveness depending on Step 1 class.

• Main limitation: departure from intent-to-treat introduces possible confounding.

ALLHAT

Antihypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack Trial (ALLHAT)

• Practice-based, randomized trial conducted at 623 N. American & Caribbean sites

• Antihypertensive component– 42,418 high-risk hypertensives >= 55

years– whether newer agents reduce incidence

of CHD compared to a diuretic– double-blind– no placebo

ALLHAT

Major Outcomes

• Nonfatal MI/CHD death (primary)

• All-cause mortality

• Stroke

• Combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina

• Combined CVD – combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated heart failure (HF), hospitalized or outpatient PAD

ALLHAT

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 TrialALLHAT

Year 1 Cohort Criteria

• On only Step 1 (blinded) therapy at the year 1 (first annual) follow-up visit

• Have not had a cardiovascular event during the first year following randomization

• Have at least one follow-up visit following the first annual visit

ALLHAT

Percent Remaining on Step 1 Monotherapy at Subsequent Annual

Visits

Step 1 Drug Year 2 Year 3 Year 4 Year 5 Yrs. 1-5

Chlorthalidone (n=7387)

77.7 77.6 77.9 77.1 36.2

Amlodipine (n=4275)

75.4 77.1 76.9 75.2 33.6

Lisinopril (n=3638)

73.9 75.3 76.2 73.8 31.3

Doxazosin (n=3180)

71.6 72.9 72.1 70.6 26.6

ALLHAT

n=number in year 1 cohort

Cox Regression Analyses• Baseline variables

– Age, gender, race, ethnicity, SBP, DBP, previous antihypertensive med use, aspirin use

– History of atherosclerotic CVD, coronary revascularization, diabetes, CHD, LVH, smoking

– Serum potassium, creatinine, total & HDL cholesterol, fasting glucose and triglycerides

• Time-dependent variables– On/off Step 1 monotherapy, SBP, DBP, serum

potassium, creatinine, total cholesterol– Variables updated annually– Missing value values from previous year brought

forward

ALLHAT

Baseline CharacteristicsC A L D

No. randomized 7387 4275 3638 3180

Age, yr, mean 66.7 66.6 66.5 66.6

% women 48.8 47.9 45.2* 46.2*

Race, %

White 57.5 59.0 64.5* 62.2*

Black 37.1 36.2 29.9 32.6

Other 5.4 4.8 5.7 5.2

ALLHAT

*p<0.05; overall race distribution significantly different in lisinopril and doxazosin treatment groups compared to chlorthalidone group

Baseline CharacteristicsC A L D

Previous AHT RX, % 88.3 88.0 86.9 87.5

BP, mm Hg, mean

Treated 143/83 143/83 142/83 142/83

Untreated 155/89 156/90 155/89 155/88

Prior CABG/PTCA, % 9.6 9.6 11.5* 10.6

Taking aspirin, % 32.1 33.5 34.9* 34.4*

HDL-C, mg/dl, mean 47.3 47.5 46.4* 46.6

Serum potassium, mmol/l, mean

4.3 4.3 4.4* 4.4*

*p<0.05

ALLHAT

Systolic Blood Pressure

128

132

136

140

144

148

Baseline 1 year 2 years 3 years

SB

P, m

ea

n, m

m H

g

Chlor Amlod Lisin Doxaz

ALLHAT

Improvement in SBP from Baseline

-12

-10

-8

-6

-4

-2

0

Chlor Amlod Lisin Doxaz

Net

ch

ang

e in

SB

P,

mm

Hg

Year 1

Year 2

Year 3

ALLHAT

Adjusted* Analyses for Major Cardiovascular Outcomes:Amlodipine vs. Chlorthalidone

ALLHAT

Outcome HR 95% CI P

CHD (Primary) 1.16 0.99, 1.38 0.07

Mortality 1.03 0.90, 1.17 0.67

Combined CHD 1.11 0.98, 1.26 0.09

Stroke 1.06 0.84, 1.35 0.60

Combined CVD 1.14 1.03, 1.25 <0.01

Heart failure (all) 1.49 1.22, 1.82 <0.001

Heart failure (H+F) 1.55 1.24, 1.92 <0.001*Baseline-adjusted for age, gender, race, ethnicity, smoking status, BP, BP meds, LVH, aspirin use, fasting glucose, creatinine, total cholesterol, HDL cholesterol, potassium; history of ASCVD, diabetes, CHD, coronary revascularization

Adjusted* Analyses for Major Cardiovascular Outcomes:Lisinopril vs. Chlorthalidone

Outcome HR 95% CI P

CHD (Primary) 0.97 0.81, 1.17 0.75

Mortality 1.04 0.90, 1.19 0.60

Combined CHD 0.98 0.86, 1.12 0.79

Stroke 1.07 0.83, 1.37 0.59

Combined CVD 1.00 0.90, 1.11 0.99

Heart failure (all) 1.09 0.87, 1.38 0.44

Heart failure (H+F) 1.12 0.87, 1.44 0.38

ALLHAT

*Baseline-adjusted for age, gender, race, ethnicity, smoking status, BP, BP meds, LVH, aspirin use, fasting glucose, creatinine, total cholesterol, HDL cholesterol, potassium; history of ASCVD, diabetes, CHD, coronary revascularization

Adjusted* Analyses for Major Cardiovascular Outcomes:Doxazosin vs. Chlorthalidone

Outcome HR 95% CI P

CHD (Primary) 1.02 0.80, 1.30 0.88

Mortality 1.06 0.87, 1.28 0.59

Combined CHD 0.99 0.83, 1.18 0.89

Stroke 1.02 0.73, 1.42 0.91

Combined CVD 1.09 0.96, 1.25 0.18

Heart failure (all) 1.71 1.29, 2.26 <0.001

Heart failure (H+F) 1.74 1.27, 2.37 <0.001

ALLHAT

*Baseline-adjusted for age, gender, race, ethnicity, smoking status, BP, BP meds, LVH, aspirin use, fasting glucose, creatinine, total cholesterol, HDL cholesterol, potassium; history of ASCVD, diabetes, CHD, coronary revascularization

Heart Failure in ALLHAT

1.72

1.1

1.43

1.71

1.09

1.49

1.64

1.09

1.39

1.8

1.19

1.38

0 0.5 1 1.5 2

D vs C

L vs C

A vs C

Relative Risk

ALLHAT ITTBaseline-unadjustedBaseline-adjustedTime-dependent

ALLHAT

****

*

****

*P<0.05

†Time-dependent analyses adjusted for the following time-dependent variables: SBP, DBP, on/off treatment, and serum potassium, creatinine, and cholesterol. Also adjusted for baseline variables: age, gender, ethnicity, BP, LVH, smoker, aspirin use, BP meds at baseline; history of atherosclerotic cardiovascular disease, coronary revascularization, diabetes, CHD.

†

Stroke in ALLHAT

1.05

1.03

1.01

1.02

1.07

1.06

1.03

0.98

0.97

1.26

1.15

0.93

0 0.5 1 1.5

D vs C

L vs C

A vs C

Relative Risk

ALLHAT ITT

Baseline-unadjusted

Baseline-adjusted

Time-dependent

ALLHAT

*P<0.05

*

*

†Time-dependent analyses adjusted for the following time-dependent variables: SBP, DBP, on/off treatment, and serum potassium, creatinine, and cholesterol. Also adjusted for baseline variables: age, gender, ethnicity, BP, LVH, smoker, aspirin use, BP meds at baseline; history of atherosclerotic cardiovascular disease, coronary revascularization, diabetes, CHD.

†

Stroke in ALLHAT: Black Participants

1.58

1.32

1.12

1.61

1.39

1.25

1.38

1.29

1.03

1.38

1.4

0.93

0 0.5 1 1.5 2

D vs C

L vs C

A vs C

Relative Risk

ALLHAT ITT

Baseline-unadjusted

Baseline-adjusted

Time-dependent

ALLHAT

*P<0.05

*

*

†Time-dependent analyses adjusted for the following time-dependent variables: SBP, DBP, on/off treatment, and serum potassium, creatinine, and cholesterol. Also adjusted for baseline variables: age, gender, ethnicity, BP, LVH, smoker, aspirin use, BP meds at baseline; history of atherosclerotic cardiovascular disease, coronary revascularization, diabetes, CHD.

†*

Conclusions (1)

Heart failure, increased in the assigned (intent-to-treat) Step 1 amlodipine and doxazosin treatment groups compared to the chlorthalidone group, is similarly increased in these treatment groups in this Step 1 monotherapy cohort.

ALLHAT

Conclusions (2)

The previously reported higher rates for stroke and CCVD, including heart failure, in the lisinopril group compared to the chlorthalidone group, do not reach significance in this monotherapy cohort.– The restricted cohort lessens the sample size.– BP differences are greatly diminished with this

restricted cohort.– Participants with early CVD events are not

included.

ALLHAT

Conclusions (3)

Unknown confounding factors may further influence results, and thus caution in interpretation is warranted.

ALLHAT

Alternate Slides

Heart Failure in ALLHAT

Relative Risk

A vs C L vs C D vs C

ALLHAT population (ITT) 1.38* 1.19* 1.80*

Year 1 monother. cohort: Unadjusted

1.39* 1.09 1.64*

Year 1 monother. cohort: Baseline-adjusted

1.49* 1.09 1.71*

Year 1 monother. cohort: Time-dependent†

1.43* 1.10 1.72*

ALLHAT

†Time-dependent variables: SBP, DBP, on/off treatment, and serum potassium, creatinine, and cholesterol; also adjusted for baseline variables

* P < 0.05

Stroke in ALLHAT

Relative Risk

A vs C L vs C D vs C

ALLHAT population (ITT) 0.93 1.15* 1.26*

Year 1 monother. cohort: Unadjusted

0.97 0.98 1.03

Year 1 monother. cohort: Baseline-adjusted

1.06 1.07 1.02

Year 1 monother. cohort: Time-dependent†

1.01 1.03 1.05

ALLHAT

†Time-dependent variables: SBP, DBP, on/off treatment, and serum potassium, creatinine, and cholesterol; also adjusted for baseline variables

* P < 0.05

Stroke in ALLHAT: Black Participants

Relative Risk

A vs C L vs C D vs C

ALLHAT Black population (ITT)

0.93 1.40* 1.38*

Year 1 monother. cohort: Unadjusted

1.03 1.29 1.38

Year 1 monother. cohort: Baseline-adjusted

1.25 1.39 1.61

Year 1 monother. cohort: Time-dependent†

1.12 1.32 1.58*

ALLHAT

†Time-dependent variables: SBP, DBP, on/off treatment, and serum potassium, creatinine, and cholesterol; also adjusted for baseline variables

* P < 0.05