U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

Review of Heart Failure Events in the Antihypertensive and Lipid Lowering

Treatment to Prevent Heart Attack Trial: ALLHAT Heart Failure Validation Study

Paula Einhorn, Barry Davis, Henry Black, William Cushman, John Kostis, Daniel Levy, Barry Massie, Barbara deLeon, Linda

Piller, Lara Simpson, Chuke Nwachuku

for

The ALLHAT Collaborative Research Group

Sponsored by the National Heart, Lung, and Blood Institute (NHLBI)

ALLHAT

www.allhat.org

Heart Failure Validation Study

Aimed to centrally review all hospitalized HF events in 42,418 ALLHAT participants.

ALLHAT

Randomized Design of ALLHAT BP Randomized Design of ALLHAT BP TrialTrial

42,41842,418

High-risk High-risk hypertensive hypertensive patientspatients

Consent / Consent / RandomizeRandomize

AmlodipineAmlodipine

ChlorthalidoneChlorthalidone

DoxazosinDoxazosin

LisinoprilLisinopril

Follow until death or end of study (4-8 years, mean 4.9 years)Follow until death or end of study (4-8 years, mean 4.9 years)

ALLHATALLHAT

JAMA. 2002;288:2981-2997

Participants

Hypertensive men and women Age 55 and older (mean 67) At least one additional CVD risk factor [old (>6 months) MI or stroke, LVH, h/o

type 2 diabetes, current smoker, HDL<35, or documented other ASCVD]

Excluded: h/o symptomatic HF and/or known LVEF <35%

ALLHAT

ALLHAT provides a double-blind comparison of 4 drug classes in preventing transition from hypertension to overt heart failure

ALLHAT

ALLHATHypertension and

Heart Failure

In Framingham Heart Study, hypertension was the most common risk factor for HF, antedating it in 91% of cases.

(JAMA. 1996;275:1557-1562)

In BP Lowering Treatment Trialists’ Collaboration, there were differences among drug classes in occurrence of HF. (Lancet 2003, 362:1527-35)

Hypertension Trial ALLHAT

Randomized, double-blind

Large, simple, practice-based trial

No protocol-mandated central review of HF events

Diagnoses assigned by clinic investigators guided by protocol-defined diagnostic criteria

ALLHAT HF Criteria

Must have one from each category:

Category “A” Category “B”Paroxysmal nocturnal dyspnea Rales

Orthopnea 2+ ankle edema

NYHA Classification III Tachycardia >= 120/min

Dyspnea at rest Cardiomegaly by CXR

CXR characteristic of CHF

S3 gallop

Jugular venous distention

ALLHAT Manual of Operations, 5.3.4 JAMA.1997;278:212-216

ALLHAT

Origin of the HF Validation Study

HF endpoint defined as treated in hospital or as outpatient, or fatal

A component of combined CVD (CHD, stroke, HF, PAD)

Systematic review of hospitalized HF events was initiated in 2001, on advice of the DSMB

ALLHAT

HF Validation Study ObjectivesALLHAT

Evaluate ALLHAT investigator-assigned diagnoses

Compare treatment effects to those previously reported (JAMA. 2002;288:2981-2997)

HF Validation Study

Relevant hospital records requested for 2952 hospitalizations in 2047 patients with a diagnosis of HF on admission or during hospital course Summary: face sheet, discharge /death summary,

admitting H&P, ER notes

Imaging reports: chest X-ray, cardiac catheterization, echocardiography, radionuclide imaging

Other reports: pulmonary function tests, cardiology or pulmonary consultation, autopsy

ALLHAT

HF Validation Study Definitions

ALLHAT

ALLHAT/SHEP

Traditional Framingham Criteria

Updated Framingham Criteria

Reviewers’ global clinical judgment

2962 hospital records for 2045 patients received.

2811 records of 1951 patients suitable for review.

Abstracted by cardiology fellows blinded to treatment assignment.

Each record independently reviewed by two reviewers.

For algorithmic criteria (ALLHAT and Framingham), diagnoses were assigned by computer.

Reviewers’ clinical judgment entered as yes, no, don’t know.

ALLHAT HF Validation Study

Framingham HF CriteriaTwo major or one major plus two minor criteria:

MajorParoxysmal nocturnal dyspnea

Jugular venous distention

Rales

Cardiomegaly on CXR

Acute pulmonary edema

S3 gallop

Central venous pressure

Circ. time >25 seconds

Hepatojugular reflux

Autopsy findings: pulmonary edema, congestion, or cardiomegaly

MinorBilateral ankle edema

Nocturnal cough

Dyspnea on exertion

Hepatomegaly

Pleural effusion

Vital capacity 1/3 from max.

Tachycardia > 120/min.

Major or minorWeight loss > 4.5 kg in 5 days in response to treatment of HF

KKL Ho et al, Circulation 88:107, 1993

ALLHAT

Updated Framingham CriteriaRequire 2 major or 1 major plus 2 minor criteria;

one has to be diagnostic and one clinical Part 1: Clinical Findings

Major

PND or orthopnea

Jugular Venous Distention

Pulmonary rales

S3 gallop

Hepatojugular reflux

Diuresis of 10 lbs or 5 kg in response to diuretic treatment with clinical improvement in congestive symptoms

Minor

Bilateral ankle edema

Nocturnal cough

Dyspnea on exertion

Hepatomegaly

ALLHAT

Updated Framingham CriteriaRequire 2 major or 1 major plus 2 minor criteria;

one has to be diagnostic and one clinical Part 2: Diagnostic Findings

MajorAcute pulmonary edema on CXR

PCWP>= 20 mm Hg

LVEF =< 35%

Cardiac Index < 2.0

Evidence of severe valvular disease

Pulmonary edema, congestion, or cardiomegaly on autopsy

MinorPleural effusion or vascular engorgement or redistribution on CXR

PCWP 16-19 mm Hg

LVEF 36 – 44%

Cardiac Index 2.0 – 2.4

Evidence of moderate valvular disease

ALLHAT

Percent agreement with investigator-assigned

diagnosis

Data refer to percentage of participants with at least one event of hospitalized or fatal heart failure that meet the criteria by at least one of the reviewers.

ALLHAT

0102030405060708090

100

ALLHAT

Fram

ingham

1

Fram

ingham

2

Rev

iewer

s

% a

gre

eme

nt

Percent Agreement with investigator-assigned diagnosisALLHAT

Chlor Amlod Lisin TOTAL

N (patients with event reviewed)

617 508 415 1093

ALLHAT 1 69% 73% 72% 71%

ALLHAT 2 69% 72% 71% 70%

ALLHAT 3 66% 69% 70% 68%

ALLHAT 4 56% 58% 56% 57%

Framingham 1 79% 81% 79% 80%

Framingham2 72% 73% 71% 72%

Reviewers agree HF 82% 86% 84% 84%

Percent Agreement with investigator-assigned diagnosisALLHAT

Chlor Dox TOTAL

N (patients with event reviewed)

418 411 829

ALLHAT 1 67% 69% 68%

ALLHAT 2 66% 68% 67%

ALLHAT 3 64% 67% 65%

ALLHAT 4 53% 53% 53%

Framingham 1 77% 76% 77%

Framingham2 69% 69% 69%

Reviewers agree HF 80% 83% 82%

HF Validation StudyVerification of Treatment Effects

For the various Validation Study definitions of HF, relative risks and 95% CIs were calculated using first events confirmed by a given definition.

ALLHAT

0.50 1 2

HF* 1.19 (1.07 - 1.31)

Hosp/fatal HF 1.10 (0.98 - 1.23)

ALLHAT 1 1.18 (1.02 - 1.36)

ALLHAT 2 1.18 (1.02 - 1.36)

ALLHAT 3 1.21 (1.04 - 1.40)

ALLHAT 4 1.13 (0.96 - 1.33)

Framingham 1 1.13 (0.99 - 1.30)

Framingham 2 1.12 (0.97 - 1.30)

Reviewer agree 1.15 (1.01 - 1.32)

Favors Lisinopril Favors Chlorthalidone

Definition, Relative Risk and 95% Confidence Intervals

Validation Study ACEI versus diuretic

ALLHAT

•RR estimates calculated from 2-by-2 table•Pre-specified endpoint of treated in hospital or as outpatient or fatal

0.50 1 2

HF* 1.37 (1.24 - 1.50)

Hosp/fatal HF 1.35 (1.21 - 1.50)

ALLHAT 1 1.46 (1.27 - 1.68)

ALLHAT 2 1.46 (1.27 - 1.67)

ALLHAT 3 1.45 (1.26 - 1.67)

ALLHAT 4 1.45 (1.24 - 1.69)

Framingham 1 1.42 (1.25 - 1.62)

Framingham 2 1.41 (1.23 - 1.61)

Reviewer agree 1.45 (1.28 - 1.64)

Definition, Relative Risk and 95% Confidence Intervals

Validation Study CCB versus diuretic

Favors Amlodipine Favors Chlorthalidone

ALLHAT

•Pre-specified endpoint of treated in hospital or as outpatient or fatal•RR estimates calculated from 2-by-2 table

HF* 1.77 (1.58 - 1.97)

Hosp/fatal HF 1.60 (1.41 - 1.81)

ALLHAT 1 1.71 (1.45 - 2.01)

ALLHAT 2 1.70 (1.45 - 2.01)

ALLHAT 3 1.72 (1.46 - 2.04)

ALLHAT 4 1.67 (1.39 - 2.01)

Framingham 1 1.63 (1.40 - 1.91)

Framingham 2 1.64 (1.40 - 1.93)

Reviewer agree 1.72 (1.48 - 1.99)

0.50 1 2 3

Validation Study α-blocker versus diuretic

Definition, Relative Risk and 95% Confidence Intervals

Favors Doxazosin Favors Chlorthalidone•Pre-specified endpoint of treated in hospital or as outpatient or fatal•RR estimates calculated from 2-by-2 table

ALLHAT

Summary An independent review of hospital records

showed a high degree of agreement with the diagnoses assigned by ALLHAT investigators

(71 – 84% agreement)

Relative risks calculated for several stringent definitions of HF confirm superiority of a thiazide-type diuretic over a CCB, an ACE-I and an alpha-blocker in preventing the onset of symptomatic HF in hypertensive patients with at least one additional risk factor.

ALLHAT

Implications

HF is a costly and deadly complication of hypertension

Thiazide-type diuretics have greater efficacy for HF prevention and should be considered first-step therapy for prevention of HF in high risk patients with hypertension

ALLHAT