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