major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone

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• ≤ 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn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