Heart Failure With Preserved And Heart Failure With Preserved And Impaired Systolic Left Ventricular Impaired Systolic Left Ventricular

Function In ALLHATFunction In ALLHAT

JB Kostis, B Davis, L Simpson, H Black, W Cushman, JB Kostis, B Davis, L Simpson, H Black, W Cushman, P Einhorn, M Farber, C Ford, D Levy, B Massie, S NawazP Einhorn, M Farber, C Ford, D Levy, B Massie, S Nawaz

For The ALLHAT Collaborative Research GroupFor The ALLHAT Collaborative Research Group

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

Randomized Design of ALLHAT BP Trial

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

Rationale for the Heart Failure Rationale for the Heart Failure Validation Study: BackgroundValidation Study: Background

Early termination of the doxazosin arm February 2000, due to:Early termination of the doxazosin arm February 2000, due to: 25% higher risk of CVD events in doxazosin compared to 25% higher risk of CVD events in doxazosin compared to

chlorthalidone, mostly driven by two-fold increase in HFchlorthalidone, mostly driven by two-fold increase in HF a very low probability of finding a significant difference for a very low probability of finding a significant difference for

the primary outcome by the scheduled trial endthe primary outcome by the scheduled trial end

Higher risk of HF in amlodipine and lisinopril arms compared Higher risk of HF in amlodipine and lisinopril arms compared with chlorthalidonewith chlorthalidone

ALLHAT DSMB recommended that this study be doneALLHAT DSMB recommended that this study be done

Early termination of the doxazosin arm February 2000, due to:Early termination of the doxazosin arm February 2000, due to: 25% higher risk of CVD events in doxazosin compared to 25% higher risk of CVD events in doxazosin compared to

chlorthalidone, mostly driven by two-fold increase in HFchlorthalidone, mostly driven by two-fold increase in HF a very low probability of finding a significant difference for a very low probability of finding a significant difference for

the primary outcome by the scheduled trial endthe primary outcome by the scheduled trial end

Higher risk of HF in amlodipine and lisinopril arms compared Higher risk of HF in amlodipine and lisinopril arms compared with chlorthalidonewith chlorthalidone

ALLHAT DSMB recommended that this study be doneALLHAT DSMB recommended that this study be done

ALLHAT

Heart Failure Validation Study: Heart Failure Validation Study: Design and MethodsDesign and Methods

Protocol developed in collaboration with heart failure Protocol developed in collaboration with heart failure experts.experts.

Additional documentation collected for all hospitalized Additional documentation collected for all hospitalized heart failure events.heart failure events.

Documentation reviewed by cardiology fellows (blinded to Documentation reviewed by cardiology fellows (blinded to treatment assignment), for signs, symptoms, past history, treatment assignment), for signs, symptoms, past history, concomitant conditions, procedures, treatments.concomitant conditions, procedures, treatments.

Analyses performed using computer algorithm to Analyses performed using computer algorithm to determine whether each case met ALLHAT or determine whether each case met ALLHAT or Framingham criteria.Framingham criteria.

Protocol developed in collaboration with heart failure Protocol developed in collaboration with heart failure experts.experts.

Additional documentation collected for all hospitalized Additional documentation collected for all hospitalized heart failure events.heart failure events.

Documentation reviewed by cardiology fellows (blinded to Documentation reviewed by cardiology fellows (blinded to treatment assignment), for signs, symptoms, past history, treatment assignment), for signs, symptoms, past history, concomitant conditions, procedures, treatments.concomitant conditions, procedures, treatments.

Analyses performed using computer algorithm to Analyses performed using computer algorithm to determine whether each case met ALLHAT or determine whether each case met ALLHAT or Framingham criteria.Framingham criteria.

ALLHAT

Heart failure developing in patients with hypertension is Heart failure developing in patients with hypertension is associated either with preserved or with impaired left associated either with preserved or with impaired left ventricular systolic function.ventricular systolic function.

ALLHAT provides the to examine occurrence and ALLHAT provides the to examine occurrence and differences in symptoms, signs and case fatality of heart differences in symptoms, signs and case fatality of heart failure with preserved or impaired left ventricular systolic failure with preserved or impaired left ventricular systolic function.function.

Heart failure developing in patients with hypertension is Heart failure developing in patients with hypertension is associated either with preserved or with impaired left associated either with preserved or with impaired left ventricular systolic function.ventricular systolic function.

ALLHAT provides the to examine occurrence and ALLHAT provides the to examine occurrence and differences in symptoms, signs and case fatality of heart differences in symptoms, signs and case fatality of heart failure with preserved or impaired left ventricular systolic failure with preserved or impaired left ventricular systolic function.function.

IntroductionIntroduction

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

HF With Preserved And Impaired HF With Preserved And Impaired Systolic Left Ventricular FunctionSystolic Left Ventricular Function

To verify the heart failure outcomes of ALLHAT, all To verify the heart failure outcomes of ALLHAT, all available hospitalized heart failure events reported by available hospitalized heart failure events reported by ALLHAT Investigators were systematically reviewed. ALLHAT Investigators were systematically reviewed.

Estimate of left ventricular ejection fraction by contrast Estimate of left ventricular ejection fraction by contrast ventriculography, echocardiography or radionuclide ventriculography, echocardiography or radionuclide study was available in 928 (66%) of 1,300 first study was available in 928 (66%) of 1,300 first hospitalized heart failure events meeting ALLHAT hospitalized heart failure events meeting ALLHAT criteria.criteria.

To verify the heart failure outcomes of ALLHAT, all To verify the heart failure outcomes of ALLHAT, all available hospitalized heart failure events reported by available hospitalized heart failure events reported by ALLHAT Investigators were systematically reviewed. ALLHAT Investigators were systematically reviewed.

Estimate of left ventricular ejection fraction by contrast Estimate of left ventricular ejection fraction by contrast ventriculography, echocardiography or radionuclide ventriculography, echocardiography or radionuclide study was available in 928 (66%) of 1,300 first study was available in 928 (66%) of 1,300 first hospitalized heart failure events meeting ALLHAT hospitalized heart failure events meeting ALLHAT criteria.criteria.

Methods

ALLHAT

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

45%

55%

HF by EF level <50% vs. >50%

N=928

EF>50%EF<50%

45%

HF With Preserved And Impaired Systolic Left Ventricular Function

29%

12%25%

34%

ALLHAT

HF by EF level N=1399

EF N/A

EF<40%

EF>50%

EF 40-49%

37%

18%

45%37%

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

HF by EF level(% of those with available EF) N=928

EF<40%

EF 40-49%

EF>50%

HF With Preserved And Impaired Systolic Left Ventricular Function

BaselineCharacteristics

Normal ImpairedP value

Normal vsImpaired

Total ALLHAT

Age 69.7 69.6 0.91 66.9

Ethnicity White non-Hispanic Black non-Hispanic Other

60.9% 31.5%7.6%

58.5% 34.2%7.3%

0.75 47.1%32.3%4.9%

Women 51.2% 37.5% <0.001 46.8%

Current Smoker 18.7% 19.2% 0.86 21.9%

Treated 95.0% 92.5% 0.12 90.2%

Atherosclerotic CVD 61.4% 64.4% 0.34 51.6%

ST dep. or T Wave Invers. 11.1% 12.2% 0.39 10.3%

Type II Diabetes 50.2% 50.2% 0.99 36.0%

LVH by ECG 18.7% 20.6% 0.48 16.4%

LVH by ECHO 6.6% 4.9% 0.27 4.5%

ALLHAT

HF With Preserved And Impaired Systolic Left Ventricular Function

BaselineCharacteristics

Normal ImpairedP value

Normal vs.Impaired

Total ALLHAT

History of CHD 32.5% 38.2% 0.07 25.6%Blood PressureSBP meanDBP mean

149.680.7

147.981.6

0.100.18

146.384.0

Fasting Glucose mean>126 mg/dL

140.840.5%

144.046.7%

0.650.10

123.029.1%

LDL mean 133.4 137.5 0.14 135.8HDL mean<35 mg/dL

45.222.1%

42.529.3%

0.0030.02

46.819.2%

Triglyceride mean 182.7 189.8 0.44 175.7

ALLHAT

Symptoms ofHeart Failure

Normal ImpairedP value

Normal vs.Impaired

%Missing

PND 29.4% 35.8% 0.04 56.5%

Orthopnea 41.7% 45.5% 0.25 45.8%

Dyspnea at rest 50.7% 49.6% 0.73 45.6%

DOE 69.0% 67.4% 0.61 30.9%

NYHA Class III 64.0% 57.1% 0.03 39.2%

Night Cough 11.6% 8.1% 0.07 82.0%

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

Signs of Heart Failure Normal Impaired

P valueNormal vs.Impaired

%Missing

Ankle Edema 2+ 37.9% 26.5% 0.0002 15.3%

Bilateral Ankle Edema 67.1% 54.2% 0.0001 10.9%

Tachycardia 120+ 11.8% 13.4% 0.47 28.7%

Jugular Venous Distention 36.3% 37.2% 0.78 28.2%

Increased Venous Pressure >8 AND <16 CM H2O 10.9% 9.5% 0.48 61.6%

Hepatojugular Reflux 2.6% 4.3% 0.15 90.9%

Rales 73.7% 76.5% 0.33 11.5%

S3 Gallop 10.0% 19.6% <0.0001 39.9%

Hepatomegaly 2.4% 5.7% 0.01 50.4%

Cardiomegaly 60.0% 62.8% 0.37 27.7%

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

Signs of Heart Failure Normal Impaired

P value Normal vs.Impaired

%Missing

Acute Pulmonary EdemaNo

28.4%13.7%

30.6%14.2%

0.47 56.4%

Pleural EffusionNo

35.1%16.4%

40.7%13.2%

0.08 47.2%

Pulmonary VascularEngorgementRedistribution

39.6%16.4%

37.2%22.1%

0.450.03

54.1%73.9%

X-Ray Characteristic of HFReviewer OpinionReport

48.3%50.7%

52.6% 55.5%

0.200.14

39.9%36.6%

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

26.5 41.6 31.9

28.6 39.9 31.4

28.6 39.4 31.9

33.7 33.2 34.7

29.9 23.3 36.2

0% 20% 40% 60% 80% 100%

CHLOR

DOX

.

CHLOR

AML

LIS*

NL EF Low EF EF N/A

EF Range by Drug

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

*lisinopril vs. chlorthalidone p=0.04

38.9 61.1

41.7 58.2

42.1 57.9

46.9 53.1

52.6 47.4

0% 20% 40% 60% 80% 100%

CHLOR

DOX

.

CHLOR

AML

LIS*

NL EF Low EF

EF Range by Drug; % of Those With Available EF

HF With Preserved And Impaired Systolic Left Ventricular FunctionALLHAT

* lis vs. chlor, p=0.02

24.8

3.4

30.3

6.8

0.0

5.010.0

15.0

20.025.0

30.0

35.040.0

NL EF Low EF

Death after HF Death with HF

Vital Status (% Dead)

28.1

37.1P=0.004

P=0.02

P=0.06

HF With Preserved And Impaired Systolic Left Ventricular Function

ALLHAT Total

0

20

40

60

80

CHLOR AML LIS

NL EF

Low EF

p=0.22p=0.001 p=0.31

Vital Status by Drug and EF Group

HF With Preserved And Impaired Systolic Left Ventricular Function

ALLHAT

Cumulative HF Rate Among All HF Cases Using ALLHAT Criteria;

With EF by EF Class

0.00

0.20

0.40

0.60

0.80

1.00

Co

nd

itio

nal

Cu

mu

lati

ve A

LL

HA

T#1

HF

Rat

e

0 1 2 3 4 5 6 7

Time to event, y

>50%40 - 49%<40%

ALLHAT

Cumulative HF Rate Among All HF Cases Using ALLHAT Criteria;

With EF by EF Class

0.00

0.20

0.40

0.60

0.80

1.00

Co

nd

itio

nal

Cu

mu

lati

ve A

LL

HA

T#1

HF

Rat

e

0 1 2 3 4 5 6 7

Time to event, y

Normal (EF>50)

Impaired (EF<50)

ALLHAT

Cumulative HF Rate Using ALLHAT Criteria; With EF<50

0.00

0.01

0.02

0.03

Cu

mu

lati

ve A

LL

HA

T#1

HF

Rat

e

0 1 2 3 4 5 6 7

Time to event, y

ChlorthalidoneAmlodipineLisinopril

RR (95%CI) P value

A/C 1.28 (1.02-1.61) 0.03

L/C 0.90 (0.70-1.16) 0.43

ALLHAT

Cumulative HF Rate Using ALLHAT Criteria; With EF>50

0.00

0.01

0.02

0.03

Cu

mu

lati

ve A

LL

HA

T#1

HF

Rat

e

0 1 2 3 4 5 6 7

Time to event, y

ChlorthalidoneAmlodipineLisinopril

ALLHAT

RR (95%CI) P value

A/C 1.56 (1.21-2.01) 0.0005

L/C 1.38 (1.06-1.80) 0.02

Cumulative HF Rate Using ALLHAT Criteria; With EF<50

0.00

0.01

0.02

Cu

mu

lati

ve A

LL

HA

T#1

HF

Rat

e

0 1 2 3 4

Time to event, y

ChlorthalidoneDoxazosin

ALLHAT

RR (95% CI) P value

D/C 1.64 (1.27-2.12) 0.0001

Cumulative HF Rate Using ALLHAT Criteria; With EF>50

0.00

0.01

0.02

Cu

mu

lati

ve A

LL

HA

T#1

HF

Rat

e

0 1 2 3 4

Time to event, y

Chlorthalidone

Doxazosin

RR (95% CI) P value

D/C 1.84 (1.35-2.52) 0.0001

ALLHAT

Post-HF Mortality With Preserved Systolic Function (EF >50)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

Cu

mu

lati

ve P

ost

-HF

Mo

rtal

ity

Rat

e

0 1 2 3 4 5 6

Time to event, y

ChlorthalidoneAmlodipineLisinopril

RR (95%CI) P value

A/C 0.70 (0.46-1.07) 0.10

L/C 1.07 (0.74-1.54) 0.73

ALLHAT

Post-HF Mortality With Impaired Systolic Function (EF<50)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

Cu

mu

lati

ve P

ost

-HF

Mo

rtal

ity

Rat

e

0 1 2 3 4 5 6

Time to event, y

ChlorthalidoneAmlodipineLisinopril

RR (95%CI) P value

A/C 1.08 (0.82-1.42) 0.59

L/C 1.06 (0.78-1.44) 0.72

ALLHAT

Post-HF Mortality With Preserved Systolic Function (EF >50)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

Cu

mu

lati

ve P

ost

HF

Mo

rtal

ity

Rat

e

0 1 2 3 4

Time to event, y

Doxazosin

Chlorthalidone

RR (95% CI) P value

D/C 0.86 (0.47-1.58) 0.62

ALLHAT

Post-HF Mortality With Impaired Systolic Function (EF<50)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

Cu

mu

lati

ve P

ost

-HF

Mo

rtal

ity

Rat

e

0 1 2 3 4

Time to event, y

Doxazosin

Chlorthalidone

RR (95% CI) P value

D/C 0.73 (0.47-1.14) 0.17

ALLHAT

Post-HF Mortality By Systolic Function

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

Cu

mu

lati

ve A

LL

HA

T#1

HF

to

Dea

th R

ate

0 1 2 3 4 5 6Time to Event, y

Preserved Systolic Function (EF >50)

Impaired Systolic Function (EF <50)

ALLHAT

Heart Failure with preserved left ventricular systolic Heart Failure with preserved left ventricular systolic

function is common in treated patients with function is common in treated patients with hypertension (compared to heart failure with impaired hypertension (compared to heart failure with impaired systolic function).systolic function).

Heart Failure with preserved left ventricular systolic Heart Failure with preserved left ventricular systolic function is associated with more edema while heart function is associated with more edema while heart failure with impaired left ventricular systolic function is failure with impaired left ventricular systolic function is associated with signs of ventricular dilatation.associated with signs of ventricular dilatation.

Heart Failure with preserved left ventricular systolic Heart Failure with preserved left ventricular systolic function is associated with lower case fatality (than function is associated with lower case fatality (than heart failure with impaired systolic function).heart failure with impaired systolic function).

Heart Failure with preserved left ventricular systolic Heart Failure with preserved left ventricular systolic

function is common in treated patients with function is common in treated patients with hypertension (compared to heart failure with impaired hypertension (compared to heart failure with impaired systolic function).systolic function).

Heart Failure with preserved left ventricular systolic Heart Failure with preserved left ventricular systolic function is associated with more edema while heart function is associated with more edema while heart failure with impaired left ventricular systolic function is failure with impaired left ventricular systolic function is associated with signs of ventricular dilatation.associated with signs of ventricular dilatation.

Heart Failure with preserved left ventricular systolic Heart Failure with preserved left ventricular systolic function is associated with lower case fatality (than function is associated with lower case fatality (than heart failure with impaired systolic function).heart failure with impaired systolic function).

Conclusions

HF With Preserved And Impaired Systolic Left Ventricular Function

ALLHAT