major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone
DESCRIPTION
ALLHAT. Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone. Final Results From The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The ALLHAT Collaborative Research Group - PowerPoint PPT PresentationTRANSCRIPT
Major Cardiovascular Events in Hypertensive Patients Randomized
to Doxazosin vs Chlorthalidone
Final Results From The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT)
The ALLHAT Collaborative Research Group
Sponsored by the National Heart, Lung, and Blood Institute (NHLBI)
Hypertension. 2003;42:239-246
ALLHAT
AntihypertensiveTrial Design
• Randomized, double-blind, multi-center clinical trial
• Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic
• 42,418 high-risk hypertensive patients ≥ 55 years
ALLHAT
Secondary Objectives: Subgroups
Pre-specified
–Age 65+
–Women
–African-Americans
–Diabetic patients
Post-hoc
–Baseline CHD
ALLHAT
Secondary Outcomes
• 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 non-hospitalized CHF, hospitalized or outpatient PAD
• Other clinical outcomes – renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer
ALLHAT
Sites in ALLHAT
• 623 clinical sites
• United States, Canada, Puerto Rico, US Virgin Islands
• VA, private & group general medicine practices, community health centers, HMOs, specialty practices
• Variety of research experience
ALLHAT
Inclusion Criteria forAntihypertensive Trial
• Age/sex: men and women aged > 55 years
• BP eligibility:
–Untreated systolic and/or diastolic hypertension ( 140/90 mm Hg but 180/110 mm Hg at two visits)
–Treated hypertension
• ≤ 160/100 mm Hg on 1-2 antihypertensive drugs at Visit 1
• ≤ 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn
–No washout period was required in ALLHAT.
ALLHAT
ALLHAT Inclusion Criteria:Risk Factors
At least one of the following:
• Myocardial infarction or stroke: at least 6 months old, or age-indeterminate
• History of revascularization procedure
• Major ST segment depression or T-wave inversion
• Other documented ASCVD
ALLHAT
ALLHAT Inclusion Criteria: Risk Factors
At least one of the following (cont.)
• Type 2 diabetes mellitus
• HDL cholesterol < 35 mg/dL on any 2 or more determinations in past 5 years
• Left ventricular hypertrophy (past 2 years)
– ECG, or echo (septum + posterior wall thickness 25 mm)
• Current cigarette smoking
ALLHAT
Major Exclusion Criteria
• MI, stroke, or angina within 6 months
• Symptomatic CHF or ejection fraction < 35%
• Known renal insufficiency - creatinine 2 mg/dL
• Requiring diuretics, CCB, ACEI, or alpha blockers for reasons other than hypertension
ALLHAT
Sample Size Assumptions & Statistical Methods
• 83% power to detect 16% reduction in risk for primary outcome
– 99% power to detect 20% reduction with the observed event rate
• 2-sided α=.0178 (z=2.37) accounts for multiple comparisons
• Analysis according to “intent to treat”
• Cumulative event rates – Kaplan-Meier
• Differences between event curves - Log-rank tests & Cox proportional hazards (PH) model
• PH assumption tested by log-log plots, tests with treatment by time interaction
– If violated, 2 x 2 table used
ALLHAT
Randomized Design of ALLHAT
High-risk hypertensive patients
Consent / Randomize
Amlodipine
Chlorthalidone
Doxazosin
Lisinopril
Eligible for lipid-lowering
Not eligible for lipid-lowering
Consent / Randomize
Pravastatin Usual care
Follow until death or end of study (4-8 yr, ave 6 yr).
ALLHAT
Step 1Treatment Protocol
Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3*
Chlorthalidone 12.5 12.5 12.5 25
Amlodipine 2.5 2.5 5 10
Lisinopril 10 10 20 40
Doxazosin 1 2 4 8
* mg/day
ALLHAT
Step 2 Agents: Dose 1* Dose 2* Dose 3*
Reserpine 0.05 qd
or 0.1 qod
0.1 qd 0.2 qd
Clonidine (oral) 0.1 bid 0.2 bid 0.3 bid
Atenolol 25 qd 50 qd 100 qd
Step 3 Agent:
Hydralazine 25 bid 50 bid 100 bid
*All doses in mg
ALLHATStep Up
Treatment Protocol
Safety Outcomes
• Angioedema
• Hospitalization for gastrointestinal bleeding
– Records from the VA hospitalization database
– Records from the Center for Medicare & Medicaid Services (CMS) database (participants age 65 or older)
ALLHAT
Decision to Dropan ALLHAT Arm
• January 24, 2000 – NHLBI Director accepts the recommendation of an independent review group to terminate doxazosin arm
– Futility of finding a significant difference for primary outcome
– Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD outcomes
ALLHAT
Baseline Characteristics
Chlorthalidone 15,255
Doxazosin 9,061
Mean SBP/DBP 146 / 84 146 / 84
Treated, % 90 90
Mean age, y 67 67
Black, % 35 36
Women, % 47 46
Current smoking % 22 22
ASCVD, % 46 46
Type 2 diabetes, % 36 36
ALLHAT
On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group
0.0
20.0
40.0
60.0
80.0
100.0
%
Chlor 88.2 87.0 86.0 84.8
Dox 81.3 78.3 75.6 74.0
12M 24M 36M 48M
ALLHAT
Full Crossovers by Antihypertensive Treatment Group
0.0
5.0
10.0
15.0
20.0
25.0
%
Chlor 0.4 0.6 1.0 1.1
Dox 4.9 6.6 9.0 10.2
12M 24M 36M 48M
Chlorthalidone: not on assigned medicine or open-label diuretic, but on open-label alpha-blockerDoxazosin: not on assigned medicine or open-label alpha-blocker, but on open-label diuretic
ALLHAT
SBP Results by Treatment Group
130
135
140
145
150
0 6 12 18 24 30 36 42 48
Months
mm
Hg
BP
Chlorthalidone Doxazosin
ALLHAT
BL 6M 1Y 2Y 4Y
C 146.2 138.2 136.7 135.8 135.3
D 146.3 141.1 139.8 138.1 137.5
DBP Results by Treatment Group
70
75
80
85
90
0 6 12 18 24 30 36 42 48
Months
mm
Hg
BP
Chlorthalidone Doxazosin
ALLHAT
BL 6M 1Y 2Y 4Y
C 84 80.1 79.2 78.2 76.4
D 83.9 80 79.3 78.2 76.4
Vital Status by Antihypertensive Treatment Group
ALLHAT
Chlorthalidone Doxazosin
N 15,255 9,061
Lost to follow-up 545 (3.6%) 361 (4.0%)
Deaths 1,258 (8.2%) 769 (8.5%)
Observed / expected person-years
95% 95%
Co
mb
ined
CV
D E
ven
t R
ate
Years to Combined CVD Event
0 1 2 3 4 50
.1
.2
.3
.4
Combined CVD Rates by ALLHAT Treatment Group
RR (95% CI) p value
D/C 1.20 (1.13 – 1.27) <0.001
ALLHAT
ChlorthalidoneDoxazosin
Favors Doxazosin Favors Chlorthalidone
0.33 0.50 1 2 3
No CHD 1.24 (1.15, 1.34)
CHD 1.14 (1.04, 1.25)
Treated 1.18 (1.11, 1.26)
Untreated 1.39 (1.14, 1.70)
Nondiabetic 1.19 (1.10, 1.28)
Diabetic 1.22 (1.11, 1.33)
Non-Black 1.16 (1.09, 1.25)
Black 1.28 (1.16, 1.42)
Women 1.17 (1.07, 1.29)
Men 1.21 (1.13, 1.30)
Age >= 65 1.23 (1.14, 1.32)
Age < 65 1.15 (1.04, 1.27)
Total 1.20 (1.13, 1.27)
No CHD
CHD 1.14 (1.04, 1.25)
Treated 1.18 (1.11, 1.26)
Untreated 1.39 (1.14, 1.70)
Nondiabetic 1.19 (1.10, 1.28)
Diabetic 1.22 (1.11, 1.33)
Non-Black 1.16 (1.09, 1.25)
Black 1.28 (1.16, 1.42)
Women 1.17 (1.07, 1.29)
Men 1.21 (1.13, 1.30)
Age >= 65 1.23 (1.14, 1.32)
Age < 65 1.15 (1.04, 1.27)
Total 1.20 (1.13, 1.27)
RR and 95% CI forCombined CVD ALLHAT
Cu
mu
lati
ve H
F R
ate
Years to HF
0 1 2 3 4 50
.05
.1
.15
Heart Failure Rates by ALLHAT Treatment Group
RR (95% CI) p value
D/C 1.80 (1.61- 2.02) <0.001
ALLHAT
ChlorthalidoneDoxazosin
Favors Doxazosin Favors Chlorthalidone
0.33 0.50 1 2 3
No CHD 1.91 (1.64, 2.22)
CHD 1.75 (1.46, 2.11)
Treated 1.87 (1.66, 2.11)
Untreated 1.54 (0.98, 2.42)
Nondiabetic 1.88 (1.60, 2.20)
Diabetic 1.85 (1.56, 2.19)
Non-Black 1.85 (1.60, 2.14)
Black 1.84 (1.51, 2.24)
Women 1.78 (1.49, 2.14)
Men 1.89 (1.62, 2.20)
Age >= 65 1.89 (1.65, 2.17)
Age < 65 1.76 (1.40, 2.22)
Total 1.80 (1.61, 2.02)
0.33 0.50 1 2 3
No CHD 1.91 (1.64, 2.22)
CHD 1.75 (1.46, 2.11)
Treated 1.87 (1.66, 2.11)
Untreated 1.54 (0.98, 2.42)
Nondiabetic 1.88 (1.60, 2.20)
Diabetic 1.85 (1.56, 2.19)
Non-Black 1.85 (1.60, 2.14)
Black 1.84 (1.51, 2.24)
Women 1.78 (1.49, 2.14)
Men 1.89 (1.62, 2.20)
Age >= 65 1.89 (1.65, 2.17)
Age < 65 1.76 (1.40, 2.22)
Total 1.80 (1.61, 2.02)
RR and 95% CI forHeart Failure ALLHAT
Cu
mu
lati
ve S
tro
ke R
ate
Years to Stroke
0 1 2 3 4 50
.02
.04
.06
.08
Stroke Rates by ALLHAT Treatment Group
RR (95% CI) p value
D/C 1.26 (1.10 – 1.46) 0.001
ALLHAT
ChlorthalidoneDoxazosin
STROKE
Favors Doxazosin Favors Chlorthalidone
0.50
1.27 (1.07 - 1.52)
1.23 (0.96 - 1.58)
1.23 (1.06 - 1.43)
1.60 (0.99 - 2.59)
1.32 (1.09 - 1.60)
1.21 (0.98 - 1.51)
1.18 (0.98 - 1.42)
1.38 (1.10 - 1.73)
1.18 (0.94 - 1.49)
0.32 (0.10 - 1.59)
1.28 (1.08 - 1.51)
1.22 (0.93 - 1.61)
Non-Diabetic
No CHD
CHD
Treated
Untreated
Diabetic
Non-Black
Black
Women
Men
Age>=65
Age<65
Total 1.26 (1.00 - 1.46)
1 2
ALLHAT
Cu
mu
lati
ve C
HD
Eve
nt
Rat
e
Years to CHD Event
0 1 2 3 4 50
.03
.06
.09
.12
CHD Rates by ALLHAT Treatment Group
RR (95% CI) p value
D/C 1.03 (0.92 – 1.15) 0.62
ALLHAT
ChlorthalidoneDoxazosin
ALLHAT CHD
Favors Doxazosin Favors Chlorthalidone
0.5 1.0 2.0
1.01 (0.87 - 1.17)
1.05 (0.88 - 1.25)
1.04 (0.92 - 1.17)
0.93 (0.63 - 1.36)
1.00 (0.87 - 1.16)
1.07 (0.91 - 1.27)
1.00 (0.88 - 1.15)
1.12 (0.90 - 1.36)
1.15 (0.94 - 1.39)
0.97 (0.85 - 1.11)
1.02 (0.89 - 1.17)
1.05 (0.86 - 1.27)
1.03 (0.92 - 1.15)Total
Age<65
Age>=65
Men
Women
Black
Non-Black
Diabetic
Non-Diabetic
Untreated
Treated
CHD
No CHD
Cu
mu
lati
ve M
ort
alit
y R
ate
Years to Death
0 1 2 3 4 50
.04
.08
.12
.16
All-Cause Mortality by ALLHAT Treatment Group
RR (95% CI) p value
D/C 1.03 (0.94 – 1.13) 0.50
ALLHAT
ChlorthalidoneDoxazosin
ALLHAT TOTAL MORTALITY
Favors Doxazosin Favors Chlorthalidone
0.50 1 2
1.03 (0.93 - 1.15)
1.02 (0.88 - 1.20)
1.02 (0.93 - 1.12)
1.16 (0.86 - 1.55)
1.07 (0.95 - 1.20)
0.99 (0.86 - 1.14)
1.01 (0.90 - 1.14)
1.06 (0.92 - 1.22)
1.10 (0.95 - 1.27)
0.99 (0.88 - 1.11)
1.07 (0.97 - 1.19)
0.90 (0.75 - 1.09)
1.03 (0.84 - 1.13)Total
Age<65
Age>=65
Men
Women
Black
Non-Black
Diabetic
Non-Diabetic
Untreated
Treated
CHD
No CHD
Total
Age<65
Age>=65
Men
Women
Black
Non-Black
Diabetic
Non-diabetic
Untreated
Treated
CHD
No CHD
ALLHAT ESRD
Favors Doxazosin Favors Chlorthalidone
0.25 0.50 1 2 3 4
1.21 (0.84 - 1.76)
0.73 (0.41 - 1.32)
1.05 (0.76 - 1.44)
0.97 (0.29 - 3.33)
0.83 (0.51 - 1.35)
1.26 (0.84 - 1.88)
1.08 (0.70 - 1.67)
0.99 (0.63 - 1.55)
1.14 (0.71 - 1.85)
0.97 (0.65 - 1.44)
1.15 (0.79 - 1.68)
0.85 (0.49 - 1.48)
1.04 (0.84 – 1.76)
Biochemical ChangesALLHAT
Baseline 4 Years
Chlor Dox Chlor Dox
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
Diabetes IncidenceALLHAT
Chlorthalidone Doxazosin Difference (D-C)
Number randomized 6755 3997
Baseline (n) 6755 3997
Mean (sd) mg/dL 93.1 (11.7) 93.0 (11.5) -0.1
>= 126 mg/dL, % 0.0 0.0 0.0
24 Months (n) 2598 1496
Mean (sd) mg/dL 102.3 (26.6) 97.1 (18.9) -5.2
Mean (sd) change 8.5 (24.4) 3.1 (17.7) -5.4
>= 126 mg/dL, % 9.5 4.7 -4.8
48 Months (n) 773 467
Mean (sd) mg/dL 104.0 (29.4) 99.7 (25.1) -4.3
Mean (sd) change 9.2 (27.1) 5.1 (22.9) -4.1
>= 126 mg/dL, % 10.6 8.8 -1.8
Final Results Confirm That for Doxazosin / Chlorthalidone:
• 20% ↑ risk of combined CVD
• 80% ↑ risk of heart failure
• 26% ↑ risk of stroke
• No difference for CHD or for total mortality
ALLHAT
Increased risk for some CV events for doxazosin in spite of lower total cholesterol and lower fasting glucose.
Conclusions
Chlorthalidone is superior to doxazosin for:
Hypertension control Drug compliance Reduction of cardiovascular complications
In addition, chlorthalidone is much less expensive
ALLHAT
Lessons Learned - 1
• For some drugs, BP lowering is an inadequate marker (surrogate) of health benefits in hypertension
• Antihypertensive drugs can have important non-BP actions that may alter the benefit of BP lowering
ALLHAT
Lessons Learned - 2
• Comparative outcome trials, like ALLHAT, are essential for documenting optimal drug benefit / risk balance and for guiding the practice of medicine
• All major health outcomes of a treatment should be evaluated
ALLHAT
Recommendations
• Chlorthalidone (diuretic) is the recommended drug of choice for initial antihypertensive treatment in high risk hypertensive patients.
• Doxazosin is not recommended as first-line therapy in hypertension.
ALLHAT
Additional Comments
• ALLHAT does not allow an assessment of the effect of doxazosin compared with placebo on the incidence of CVD.
• The use of doxazosin as a step-up drug for treating hypertension was not tested in this trial.
• These findings are likely to apply to all alpha-blockers.
ALLHAT