Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone

1
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. 200342239-246
2
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

3
Secondary Objectives Subgroups
4
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

5
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

6
Inclusion Criteria forAntihypertensive Trial

• Age/sex men and women aged gt 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  have been partially withdrawn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.

7
ALLHAT Inclusion CriteriaRisk 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

8
ALLHAT Inclusion Criteria Risk Factors

• At least one of the following (cont.)
• Type 2 diabetes mellitus
• HDL cholesterol lt 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

9
Major Exclusion Criteria

• MI, stroke, or angina within 6 months
• Symptomatic CHF or ejection fraction lt 35
• Known renal insufficiency - creatinine ? 2 mg/dL
• Requiring diuretics, CCB, ACEI, or alpha blockers
  for reasons other than hypertension

10
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 a.0178 (z2.37) 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

11
Randomized Design of ALLHAT
Amlodipine Chlorthalidone Doxazosin Lisinopril
High-risk hypertensive patients
Consent / Randomize
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).
12
Step 1Treatment Protocol
13
Step UpTreatment Protocol
14
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)

15
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

16
Baseline Characteristics
17
On Step 1 or Equivalent Treatment by
Antihypertensive Treatment Group
18
Full Crossovers by Antihypertensive Treatment
Group
Chlorthalidone not on assigned medicine or
open-label diuretic, but on open-label
alpha-blocker Doxazosin not on assigned
medicine or open-label alpha-blocker, but on
open-label diuretic
19
SBP Results by Treatment Group
20
DBP Results by Treatment Group
21
Vital Status by Antihypertensive Treatment Group
22
Combined CVD Rates by ALLHAT Treatment Group
.4
.3
Chlorthalidone Doxazosin
Combined CVD Event Rate
.2
.1
0
0
1
2
3
4
5
Years to Combined CVD Event
23
RR and 95 CI for Combined CVD
Total
1.20 (1.13, 1.27)
Total
1.20 (1.13, 1.27)
Age lt 65
1.15 (1.04, 1.27)
Age lt 65
1.15 (1.04, 1.27)
Age gt 65
1.23 (1.14, 1.32)
Age gt 65
1.23 (1.14, 1.32)
Men
1.21 (1.13, 1.30)
Men
1.21 (1.13, 1.30)
Women
1.17 (1.07, 1.29)
Women
1.17 (1.07, 1.29)
Black
1.28 (1.16, 1.42)
Black
1.28 (1.16, 1.42)
Non
-
Black
1.16 (1.09, 1.25)
Non
-
Black
1.16 (1.09, 1.25)
Diabetic
1.22 (1.11, 1.33)
Diabetic
1.22 (1.11, 1.33)
Nondiabetic
1.19 (1.10, 1.28)
Nondiabetic
1.19 (1.10, 1.28)
Untreated
1.39 (1.14, 1.70)
Untreated
1.39 (1.14, 1.70)
Treated
1.18 (1.11, 1.26)
Treated
1.18 (1.11, 1.26)
CHD
1.14 (1.04, 1.25)
CHD
1.14 (1.04, 1.25)
No CHD
1.24 (1.15, 1.34)
No CHD
0.33
0.50
1
2
3
Favors Doxazosin
Favors Chlorthalidone
24
Heart Failure Rates by ALLHAT Treatment Group
.15
Chlorthalidone Doxazosin
.1
Cumulative HF Rate
.05
0
0
1
2
3
4
5
Years to HF
25
RR and 95 CI for Heart Failure
Total
1.80 (1.61, 2.02)
Total
1.80 (1.61, 2.02)
Age lt 65
1.76 (1.40, 2.22)
Age lt 65
1.76 (1.40, 2.22)
Age gt 65
1.89 (1.65, 2.17)
Age gt 65
1.89 (1.65, 2.17)
Men
1.89 (1.62, 2.20)
Men
1.89 (1.62, 2.20)
Women
1.78 (1.49, 2.14)
Women
1.78 (1.49, 2.14)
Black
1.84 (1.51, 2.24)
Black
1.84 (1.51, 2.24)
Non
-
Black
1.85 (1.60, 2.14)
Non
-
Black
1.85 (1.60, 2.14)
Diabetic
1.85 (1.56, 2.19)
Diabetic
1.85 (1.56, 2.19)
Nondiabetic
1.88 (1.60, 2.20)
Nondiabetic
1.88 (1.60, 2.20)
Untreated
1.54 (0.98, 2.42)
Untreated
1.54 (0.98, 2.42)
Treated
1.87 (1.66, 2.11)
Treated
1.87 (1.66, 2.11)
CHD
1.75 (1.46, 2.11)
CHD
1.75 (1.46, 2.11)
No CHD
1.91 (1.64, 2.22)
No CHD
1.91 (1.64, 2.22)
0.33
0.50
1
2
3
0.33
0.50
1
2
3
Favors Doxazosin Favors
Chlorthalidone
26
Stroke Rates by ALLHAT Treatment Group
.08
.06
Chlorthalidone Doxazosin
.04
Cumulative Stroke Rate
.02
0
0
1
2
3
4
5
Years to Stroke
27
STROKE
1.26 (1.00 - 1.46)
1.22 (0.93 - 1.61)
1.28 (1.08 - 1.51)
0.32 (0.10 - 1.59)
1.18 (0.94 - 1.49)
1.38 (1.10 - 1.73)
1.18 (0.98 - 1.42)
1.21 (0.98 - 1.51)
1.32 (1.09 - 1.60)
1.60 (0.99 - 2.59)
1.23 (1.06 - 1.43)
1.23 (0.96 - 1.58)
1.27 (1.07 - 1.52)
0.50
1
2
Favors Doxazosin
Favors Chlorthalidone
28
CHD Rates by ALLHAT Treatment Group
.12
.09
Chlorthalidone Doxazosin
.06
Cumulative CHD Event Rate
.03
0
0
1
2
3
4
5
Years to CHD Event
29
CHD
1.03 (0.92 - 1.15)
1.05 (0.86 - 1.27)
1.02 (0.89 - 1.17)
0.97 (0.85 - 1.11)
1.15 (0.94 - 1.39)
1.12 (0.90 - 1.36)
1.00 (0.88 - 1.15)
1.07 (0.91 - 1.27)
1.00 (0.87 - 1.16)
0.93 (0.63 - 1.36)
1.04 (0.92 - 1.17)
1.05 (0.88 - 1.25)
1.01 (0.87 - 1.17)
0.5
1.0
2.0
Favors Doxazosin Favors
Chlorthalidone
30
All-Cause Mortality by ALLHAT Treatment Group
.16
.12
Chlorthalidone Doxazosin
.08
Cumulative Mortality Rate
.04
0
0
1
2
3
4
5
Years to Death
31
TOTAL MORTALITY
1.03 (0.84 - 1.13)
0.90 (0.75 - 1.09)
1.07 (0.97 - 1.19)
0.99 (0.88 - 1.11)
1.10 (0.95 - 1.27)
1.06 (0.92 - 1.22)
1.01 (0.90 - 1.14)
0.99 (0.86 - 1.14)
1.07 (0.95 - 1.20)
1.16 (0.86 - 1.55)
1.02 (0.93 - 1.12)
1.02 (0.88 - 1.20)
1.03 (0.93 - 1.15)
0.50
1
2
Favors Doxazosin Favors
Chlorthalidone
32
ESRD
1.04 (0.84 1.76)
0.85 (0.49 - 1.48)
1.15 (0.79 - 1.68)
0.97 (0.65 - 1.44)
1.14 (0.71 - 1.85)
0.99 (0.63 - 1.55)

1.08 (0.70 - 1.67)
1.26 (0.84 - 1.88)
0.83 (0.51 - 1.35)
0.97 (0.29 - 3.33)
1.05 (0.76 - 1.44)
0.73 (0.41 - 1.32)
1.21 (0.84 - 1.76)
0.25
0.50
1
2
3
4
Favors Doxazosin

Favors Chlorthalidone
33
Biochemical Changes
34
Diabetes Incidence
35
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

Increased risk for some CV events for doxazosin
in spite of lower total cholesterol and lower
fasting glucose.
36
Conclusions

• Chlorthalidone is superior to doxazosin for
• Hypertension control
• Drug compliance
• Reduction of cardiovascular complications
• In addition, chlorthalidone is much less expensive

37
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

38
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

39
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.

40
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.