Validation of Heart Failure Events in ALLHAT

Participants Assigned to Doxazosin and Chlorthalidone

L.B.Piller, B.R.Davis, J.A.Cutler, W.C.Cushman, J.T. Wright,

J.D.Williamson, F.H.Leenen, O.Randall, J.S.Golden

The University of Texas School of Public Health Houston, Texas

ALLHAT

At IssueALLHAT

The doxazosin group showed a doubling of risk of CHF compared to the chlorthalidone group (RR, 2.04; 95% CI, 1.79-2.32).

Objectives

• To describe the process by which the clinical reports of heart failure events were validated

• To describe the statistical analyses which led to the cessation of the doxazosin arm

ALLHAT

0.00

0.02

0.04

0.06

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0 1 2 3 4

Cu

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Years of Follow-up

doxazosinchlorthalidone

Congestive Heart Failure

C: 15,256D: 9,061

13,644 7,845

9,541 5,457

5,5313,089

2,4271,351

9,541 5,457

9,541 5,457

Rel Risk 2.04

p < 0.001

95% CL1.79-2.32

0 1 2 3 4

0

0.02

0.04

0.06

0.08

0.10

ALLHAT

Relative Risks and 95% CICongestive Heart Failure Doxazosin/Chlorthalidone

0.000.501.001.502.002.503.003.504.004.50

High 2.32 2.53 2.41 2.81 2.40 4.14 3.21 2.62 3.97 2.59 2.37

Low 1.79 1.51 1.78 1.47 1.58 1.11 1.67 1.49 0.85 1.76 1.67

RR 2.04 1.96 2.07 2.04 1.94 2.15 2.32 1.98 1.84 2.14 1.98

TotalAge <65

Age 65+

BNH Men

WNH Men

Hisp Men

BNH W

WNH W

Hisp W

DiabNondi

a

ALLHAT

Methods• Comparison of baseline characteristics of CHF and non-

CHF participants • Comparison of pre and post-event medical management • Endpoints Subcommittee evaluation of a sample of

hospitalized and fatal heart failure cases using study criteria

• Determination and comparison of frequency and severity of systolic dysfunction through ascertainment of ejection fractions (EF)

• Comparison of case-fatality rates and causes of death• Evaluate more stringent CHF-defined outcome

ALLHAT

Baseline Characteristics

• Do baseline characteristics differ in expected ways between participants with and without CHF, and are these differences generally similar in the doxazosin and chlorthalidone arms?

ALLHAT

Baseline Characteristics:CHF vs. Non-CHF Participants

Without CHF With CHF

C D C D

No. randomized 14848 8576 420 491

Mean age, yrs. 67 67 71 71

White Non-Hispanic 47% 46% 62% 59%

Black Non-Hispanic 32% 33% 31% 34%

Hispanic 16% 17% 4% 5%

Women 47% 47% 41% 41%

ALLHAT

Baseline Characteristics:CHF vs. Non-CHF Participants

ALLHAT

Without CHF Any CHF

C D C D

Current smoker, % 22 22 17 19

Antihypertensive RX

Treated >2 mos, % 87 87 90 92

Treated <2 mos, % 3 3 4 2

Untreated,% 10 10 7 6

BP, mm Hg, mean 146/84 146/84 148/81 149/82

LVH by ECG, % 16 16 20 20

LVH by Echo, % 4 4 5 3

Eligibility Criteria: CHF vs. Non-CHF Participants

Without CHF With CHF

C D C D

Old MI or stroke, % 23 22 38 34

CABG/Angioplasty, % 13 12 24 21

Other ASCVD, % 23 25 33 29

Diabetes, % 36 35 46 46

Low HDL, % 12 12 13 14

LVH by ECG, % 16 16 20 22

LVH by echo, % 5 5 5 4

ST depression/T wave abn., % 10 10 13 12

Current smoker, % 22 22 18 18

ALLHAT

Pre and Post-Event Treatment of Heart Failure Participants

• Was pre-heart failure event step 1 treatment compliance equivalent in the chlorthalidone and doxazosin groups?

• Were the heart failure participants in the chlorthalidone and doxazosin groups managed similarly following the heart failure events?

ALLHAT

Pre-Event Treatment ofHospitalized CHF Participants

Pre-Event Medication

Chlorthalidone Group (n=283)

Doxazosin Group (n=311)

Step 1 67% 86%

Open-label diuretic 26% 23%

Open-label Ace-I 16% 10%

Beta-blocker 19% 15%

ALLHAT

Pre-Event Treatment of Non-Hospitalized but Treated

CHF ParticipantsPre-Event Medication

Chlorthalidone Group (n=93)

Doxazosin Group

(n=145)

Step 1 78% 88%

Open-label diuretic 28% 15%

Open-label Ace-I 15% 8%

Beta-blocker 19% 15%

ALLHAT

Post-Event Treatment ofHospitalized CHF Participants

Post-Event Medication

Chlorthalidone Group (n=283)

Doxazosin Group (n=311)

Step 1 36% 45%

Open-label diuretic 58% 64%

Open-label Ace-I 39% 41%

Beta-blocker 14% 14%

ALLHAT

Post-Event Treatment of Non-Hospitalized but Treated

CHF ParticipantsPost-Event Medication

Chlorthalidone Group (n=93)

Doxazosin Group (n=145)

Step 1 58% 64%

Open-label diuretic 61% 68%

Open-label Ace-I 33% 30%

Beta-blocker 19% 22%

ALLHAT

Heart Failure Event Reporting

• Did the reports of hospitalized or fatal heart failure adhere to the study criteria?

ALLHAT

ALLHAT Study Events

• Documentation required:– Discharge summaries for

all hospitalizations– Death certificates for all

deaths

• Additional QC documentation for random 10% sample of MI’s, strokes and fatal CHD

• Routinely reviewed for accuracy and appropriateness

• Queries sent to the sites for clarification of discrepancies

• A random 10% of MI’s, strokes and fatal CHD reports reevaluated by the Endpoints Subcommittee for quality control

ManagementDocumentation

ALLHAT

Endpoint SubcommitteeEvaluation of CHF Events

• 50 cases of reported hospitalized and/or fatal CHF

• Each case reviewed by two Subcommittee members

• Criteria for confirmation of CHF as described in the Manual of Operations

ALLHAT

Criteria for CHFEvaluation*

Must have one from each category:

Category “A” Category “B”Paroxysmal nocturnal dyspnea

Rales

Dyspnea at rest Ankle edema

NYHA Classification III Tachycardia

Orthopnea Cardiomegaly by CXR

CXR characteristic of CHF

S3 gallop

Jugular venous distention

*ALLHAT Manual of Operations, 5.3.4

ALLHAT

New York Heart Association Functional Classification of Congestive Heart Failure*

I No limitations of activity; ordinary activity does not cause undue fatigue, palpitations, dyspnea or anginal pain

II Slight limitations of activity; asymptomatic at rest; ordinary activity results in fatigue, palpitations, dyspnea or anginal pain

III Marked limitations of activity; usually asymptomatic at rest; less than ordinary activity causes fatigue, palpitations, dyspnea or anginal pain

IV Inability to carry on any physical activity without discomfort; symptoms at rest; increased discomfort with any physical activity* Criteria Committee, New York Heart Association. Diseases of the heart and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. 1964:114.

Framingham Criteria for the Diagnosis of Congestive Heart Failure*

Major Criteria

Paroxysmal nocturnal dyspnea (A)

Neck vein distention (B)

Rales (B)

Cardiomegaly (B)

Acute pulmonary edema (B)

S3 gallop (B)

venous pressure (B)

+ hepatojugular reflux

Minor Criteria

Extremity edema (B)

Night cough (A)

Dyspnea on exertion (A)

Hepatomegaly

Pleural effusion (B)

Vital capacity by 1/3 of nml

Tachycardia >120 bpm (B)

Major or Minor

Weight loss >4.5 kg over 5 days’ treatment

At least two major or one major and two minor criteria are required for the diagnosis of CHF.

*KKL Ho et al, Circulation 88:107, 1993.

Endpoints Subcommittee Evaluation of CHF Sample (n=50)

Drug group CHF per 1 or both

reviewers

Not CHF per 1 or

both reviewers

Insufficient data to call CHF

Total

Chlorthalidone

9 1 2 12

Doxazosin 9 1 2 12

Amlodipine 6 2 4 12

Lisinopril 9 2 3 14

Total 33 6 11 50Cases with insufficient data: 11/50

Remaining cases with CHF: 33/39 (85%)

Remaining chlorthalidone cases with CHF: 9/10 (90%)

Remaining doxazosin cases with CHF: 9/10 (90%)

ALLHAT

Severity of Heart Failure

• What is the frequency of systolic dysfunction in doxazosin and chlorthalidone participants with heart failure?

• Is the systolic dysfunction equally severe in the chlorthalidone and doxazosin participants with heart failure?

ALLHAT

Assessment of the Severityof Hospitalized and Fatal Heart Failure

• Half of hospitalized or fatal heart failure events reviewed for ejection fractions (EF)

• If EF documented, further information sought– How was it obtained?– Was the EF equally severe across drug groups?– Given possible differences between VA and non-

VA sites in levels of diagnostic testing, was there a difference between the two groups in EF data?

ALLHAT

CHF Ejection Fraction Data

Chlorthalidone Group

Doxazosin

Group

Hospitalized or fatal events reviewed

170 191

Ejection fraction performed 79 (47%) 99 (52%)

By catheterization 17 33

By echocardiogram 60 64

By unknown means 2 2

ALLHAT

CHF Ejection Fraction Data:Hospitalized or Fatal CHF

Ejection Fraction

%

Chlorthalidone Group

Doxazosin Group

1-30 35% 51%

31-40 31% 21%

41-50 18% 12%

51-70 16% 16%

ALLHAT

CHF Ejection Fraction Data: Hospitalized or Fatal CHF (VA

Clinics)Ejection Fraction

%

Chlorthalidone Group

Doxazosin Group

1-30 38% 58%

31-40 42% 20%

41-50 8% 8%

51-70 13% 15%

ALLHAT

CHF Ejection Fraction Data: Hospitalized or Fatal CHF (Non-VA

Clinics)

Ejection Fraction

%

Chlorthalidone Group

Doxazosin Group

1-30 32% 41%

31-40 20% 22%

41-50 28% 19%

51-70 20% 19%

ALLHAT

Fatality Rates and Cause of Death

• Is all-cause mortality similar for the chlorthalidone and doxazosin participants?

• Are case-fatality rates similar and as high as expected for chlorthalidone and doxazosin participants hospitalized for heart failure?

• Are causes of deaths for chlorthalidone and doxazosin participants previously hospitalized for heart failure similarly distributed?

ALLHAT

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Years of Follow-up

doxazosinchlorthalidone

All-Cause Mortality

C: 15,268D: 9,067

13,739 8,054

10,513 6,118

5,7023,287

2,5301,481

Rel Risk 1.03

p = 0.56

95% CL0.90-1.15

ALLHAT

Cumulative Mortality forHospitalized CHF Cases

Cu

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Years Hospitalized CHF to Death

0 1 2 3 4

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.2

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.4

.5

chlorthalidone

doxazosin

ALLHAT

Causes of Death of Participants Hospitalized for CHF

Cause of DeathChlorthalidone

Group(ppts=280, deaths=52)

Doxazosin Group (ppts=317, deaths=70)

MI/CHD 25% 30%

Stroke 2% 4%

CHF 21% 17%

Other CVD 8% 10%

Total CVD deaths 56% 61%

Cancer 15% 9%

Kidney disease 2% 1%

Accident/suicide/homicide

0 1%

Other non-CVD 15% 16%

Unknown 12% 11%

ALLHAT

Fatal and Hospitalized CHF: Increased Risk?

ALLHAT

Does the more stringent CHF outcome, fatal and hospitalized CHF, show a similarly increased CHF risk in the doxazosin group compared to the chlorthalidone group?

Hospitalized or Fatal CHF

Rel Risk 95% CI

1.83 1.58-2.13

p < 0.001doxazosin

chlorthalidone

Years of Follow-up

Cu

mu

lative Even

t R

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0 0

0 1 2 3 4

0

.02

.04

.06

ALLHAT

Relative Risks and 95% CIHospitalized or Fatal Congestive Heart

Failure Doxazosin/Chlorthalidone

0.000.501.001.502.002.503.003.504.004.50

High 2.13 2.43 2.20 2.83 2.38 4.38 3.19 1.98 4.08 2.46 2.15

Low 1.58 1.32 1.56 1.35 1.45 1.01 1.49 1.02 0.82 1.58 1.41

RR 1.83 1.79 1.85 1.95 1.86 2.10 2.18 1.42 1.83 1.97 1.74

TotalAge <65

Age 65+

BNH Men

WNH Men

Hisp Men

BNH Wome

WNH Wome

Hisp Wome

Diabetic

Nondia

ALLHAT

Conclusions (1)

• The risk for the more stringent outcome of hospitalized or fatal heart failure was significantly higher in the doxazosin treatment group compared to the chlorthalidone treatment group (RR, 1.83; 95% CI, 1.58-2.13).

• Case-fatality rates for participants with heart failure were high (20% in 2 years) and similar in both groups.

• Hospital discharge data for heart failure was largely consistent with the ALLHAT definition of heart failure.

• In both groups, two thirds of the hospitalized or fatal heart failure events with ejection fraction measurements had ejection fractions of 40% or less.

ALLHAT

Conclusions (2)

• The treatment following the heart failure events in both groups was consistent with recommended treatment of heart failure in the community.

• Similar percentages of participants in both treatment groups were on step 1 medication prior to the heart failure event.

• Participants who developed heart failure had a greater history of coronary heart disease than participants who did not develop heart failure.

ALLHAT