heart failure (hf) findings: are they real?

Heart Failure (HF) Findings:Heart Failure (HF) Findings:Are They Real?Are They Real?

Stanley S. Franklin, MD, FACP, FACC

Clinical Professor of MedicineUniversity of California at IrvineAssociate Medical DirectorUCI Heart Disease Prevention ProgramIrvine, California

ALLHAT

Presenter Disclosure Information

DISCLOSURE INFORMATION:The following relationships exist related to this presentation:

Speakers bureau for: Boehringer Ingelheim, Bristol-Myers Squibb, Merck.

Consultant for: AtCor Medical, Bristol-Myers Squibb, and Merck

Stanley S. Franklin, MD, FACP, FACC, FAHA, FASN

HF ObjectivesHF Objectives

Characterize HF in ALLHAT by its antecedent risk factors Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions.and underlying conditions.

Examine occurrence of HF by treatment groups overall, in Examine occurrence of HF by treatment groups overall, in subgroups, and over time.subgroups, and over time.

Examine post-HF mortality overall and by treatment Examine post-HF mortality overall and by treatment group.group.

Characterize HF in ALLHAT by its antecedent risk factors Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions.and underlying conditions.

Examine occurrence of HF by treatment groups overall, in Examine occurrence of HF by treatment groups overall, in subgroups, and over time.subgroups, and over time.

Examine post-HF mortality overall and by treatment Examine post-HF mortality overall and by treatment group.group.

ALLHAT

Davis BH, et al. Circulation 2006;113:2201-10

Decision to StopDoxazosin Arm

Futility of finding a significant difference for primary outcome compared to chlorthalidone

Statistically significant 25 percent higher rate of major cardiovascular events, including near twofold higher rate of HF (hospitalized, treated out-of-hospital, or fatal)

ALLHAT

Blood Pressure TrialDesign ALLHAT

• Randomized, practice –based

• Double-blind (not PROBE)

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

• Randomization stratified by clinic

• Exclude: h/o symptomatic HF (stage C) and/or known LVEF <35%

Baseline CharacteristicsBaseline CharacteristicsALLHATHospitalized/Fatal HF During TrialHospitalized/Fatal HF During Trial

YesYes NoNo DifferenceDifference pp

NN 1,7731,773 31,58431,584

Age (mean)Age (mean) 70.370.3 66.766.7 +3.6+3.6 <0.001<0.001

Men, %Men, % 55.2%55.2% 53.0%53.0% +2.2%+2.2% 0.0080.008

Pre-RZ Treatment, %Pre-RZ Treatment, % 93.1%93.1% 90.0%90.0% +3.1%+3.1% 0.0040.004

SBP (mean mm Hg)SBP (mean mm Hg) 148.2148.2 146.2146.2 +2.0+2.0 <0.001<0.001

DBP (mean mm Hg)DBP (mean mm Hg) 81.881.8 84.184.1 -2.3-2.3 <0.001<0.001

Pulse (mean bpm)Pulse (mean bpm) 74.674.6 73.573.5 +1.1+1.1 <0.001<0.001

Cigarette smoking, %Cigarette smoking, % 18.3%18.3% 22.1%22.1% -3.8-3.8 <0.001<0.001

Diabetes, %Diabetes, % 49.449.4 35.435.4 +14.0%+14.0% <0.001<0.001

LVH by ECG, %LVH by ECG, % 18.4%18.4% 16.3%16.3% +2.1%+2.1% <0.001<0.001

History of CHD, %History of CHD, % 37.6%37.6% 24.7%24.7% +12.9+12.9 <0.001<0.001

BMI (mean)BMI (mean) 30.330.3 29.729.7 +0.6+0.6 <0.001<0.001


Hospitalized/ Fatal HF by ALLHAT Treatment Group

Cu

mu

lati

ve E

ven

t R

ate

Years0 1 2 3 4 5 6 7

0

.02

.04

.06

.08

.1

RRRR 95% CI95% CI

A-CA-C 1.351.35 1.21-1.501.21-1.50

L-CL-C 1.111.11 0.99-1.240.99-1.24

A-LA-L 1.231.23 1.09 – 1.381.09 – 1.38

ChlorthalidoneAmlodipineLisinopril

ALLHAT


HF Before and After 1 Year

• A test of the proportional hazards assumption for Cox regression revealed that RRs were not constant over time. Therefore, a Cox regression that used a time-dependent indicator variable (<=1 year versus >1 year) was utilized.

ALLHAT


1 2 3 4 5 6 7

.02

.04

.06

.08

.1

0

Cu

mu

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ve H

osp

/Fat

al H

F R

ate

0 .5 1

0

.01

.02

Years to Hosp/Fatal HF

ChlorthalidoneAmlodipineLisinopril

Years to Hosp/Fatal HF

0

Baseline to Year 1Baseline to Year 1

RRRR 95% CI95% CI

A-CA-C 2.222.22 1.69 – 2.911.69 – 2.91

L-CL-C 2.082.08 1.58 – 2.741.58 – 2.74

A-LA-L 1.071.07 0.82 – 1.380.82 – 1.38

> Year 1> Year 1

RRRR 95% CI95% CI

A-CA-C 1.221.22 1.08 – 1.381.08 – 1.38

L-CL-C 0.960.96 0.85 – 1.100.85 – 1.10

A-LA-L 1.271.27 1.10 – 1.461.10 – 1.46

Hospitalized/ Fatal HF by ALLHAT Treatment Group Within 1 Year and >1 YearALLHAT


1.83 (1.25 - 2.67)1.83 (1.25 - 2.67)Non-DiabeticNon-Diabetic

2.71 (1.83 - 4.02)2.71 (1.83 - 4.02)DiabeticDiabetic

2.17 (1.46 - 3.21)2.17 (1.46 - 3.21)WomenWomen

2.27 (1.56 - 3.30)2.27 (1.56 - 3.30)MenMen

2.37 (1.55 - 3.63)2.37 (1.55 - 3.63)BlackBlack

2.12 (1.49 - 3.01)2.12 (1.49 - 3.01)Non-BlackNon-Black

2.06 (1.51 - 2.80)2.06 (1.51 - 2.80)Age Age ≥≥ 65 65

2.89 (1.62 - 5.17)2.89 (1.62 - 5.17)Age < 65Age < 65

2.22 (1.69 - 2.91)2.22 (1.69 - 2.91)TotalTotal

0.50 1 2 3 4 5 6

FavorsAmlodipine

FavorsChlorthalidone

Relative Risk(95% CI)

Hospitalized/fatal HF in Subgroups -Amlodipine / Chlorthalidone Relative Risks

from Baseline to 1 Year of Follow-up ALLHAT


Hospitalized/fatal HF in Subgroups -Amlodipine / Chlorthalidone Relative Risks

After 1 Year of Follow-up

0.50 1 2 3 4 5 6

FavorsAmlodipine



1.21 (1.02 - 1.43)1.21 (1.02 - 1.43)Non-DiabeticNon-Diabetic

1.23 (1.04 - 1.46)1.23 (1.04 - 1.46)DiabeticDiabetic

1.16 (0.97 - 1.39)1.16 (0.97 - 1.39)WomenWomen

1.28 (1.09 - 1.50)1.28 (1.09 - 1.50)MenMen

1.28 (1.03 - 1.58)1.28 (1.03 - 1.58)BlackBlack

1.20 (1.04 - 1.39)1.20 (1.04 - 1.39)Non-BlackNon-Black

1.17 (1.02 - 1.35)1.17 (1.02 - 1.35)Age Age ≥≥ 65 65

1.38 (1.10 - 1.73)1.38 (1.10 - 1.73)Age < 65Age < 65

1.22 (1.08 - 1.38)1.22 (1.08 - 1.38)TotalTotal

ALLHAT


Hospitalized/fatal HF in Subgroups -Lisinopril / Chlorthalidone Relative Risks

from Baseline to 1 Year of Follow-up

2.16 (1.50 - 3.10)2.16 (1.50 - 3.10)

1.99 (1.31 - 3.05)1.99 (1.31 - 3.05)

2.40 (1.63 - 3.54)2.40 (1.63 - 3.54)

1.80 (1.22 - 2.67)1.80 (1.22 - 2.67)

2.15 (1.39 - 3.33)2.15 (1.39 - 3.33)

2.04 (1.43 - 2.90)2.04 (1.43 - 2.90)

1.98 (1.45 - 2.70)1.98 (1.45 - 2.70)

2.53 (1.39 - 4.59)2.53 (1.39 - 4.59)

2.08 (1.58 - 2.74)2.08 (1.58 - 2.74)

0.50 1 2 3 4 5


FavorsLisinopril


Non-DiabeticNon-Diabetic

DiabeticDiabetic

WomenWomen

MenMen

BlackBlack

Non-BlackNon-Black

Age Age ≥≥ 65 65

Age < 65Age < 65

TotalTotal

ALLHAT


Non-DiabeticNon-Diabetic

DiabeticDiabetic

WomenWomen

MenMen

BlackBlack

Non-BlackNon-Black

Age Age ≥≥ 65 65

Age < 65Age < 65

TotalTotal

0.93 (0.77 - 1.12)0.93 (0.77 - 1.12)

1.01 (0.84 - 1.22)1.01 (0.84 - 1.22)

0.89 (0.73 - 1.09)0.89 (0.73 - 1.09)

1.02 (0.86 - 1.21)1.02 (0.86 - 1.21)

1.10 (0.88 - 1.37)1.10 (0.88 - 1.37)

0.90 (0.77 - 1.06)0.90 (0.77 - 1.06)

0.97 (0.84 - 1.13)0.97 (0.84 - 1.13)

0.95 (0.74 - 1.23)0.95 (0.74 - 1.23)

0.96 (0.85 - 1.10)0.96 (0.85 - 1.10)

0.50 1 2


FavorsLisinopril


Hospitalized/fatal HF in Subgroups -Lisinopril / Chlorthalidone Relative Risks

After 1 Year of Follow-upALLHAT


ALLHAT

1. Can the early divergence of HF curves in the treatment arms be

explained by the preferential discontinuation of diuretics upon entry into ALLHAT?

4 Unanswered Questions

Potential Confounders

• Confounders by indication: why was the patient placed on a specific class of drug prior to participation in the study?

• Missing data: approximately one third of HF cases lacked information on specific drugs used prior to entry into ALLHAT

ALLHAT

Grimm R, et al J Am Cardiol Coll 2007;49:350A

Baseline Characteristics of Participants with HF within First Year Following RandomizationALLHAT

With Prior BP Med Data

Without Prior BP Med Data

P Value

Hx of CHD, % 40.7 33.7 NS

Hx of cor. revasc., % 20.7 18.0 NS

Hx of diabetes, % 45.8 48.3 NS

Cigarette smoker,% 20.4 14.6 NS

LVH on ECG, % 24.4 22.5 NS

Tchol., mean, mg/dL 216.0 212.4 NS

Fast. trig.,mean, mg/dL 180.8 161.8 NS


Validation of Case-Only Analyses

• A technique know as case-only analyses was used to examine if there was interaction between prior drugs and treatment effects.

• Does “any prior meds (yes/no)” have the same interaction effect with treatment on outcomes in a “cases and non-cases” analysis versus a “case only analysis” ?

ALLHAT


Interaction OR between prior use of diuretic and treatment effects in HF

• Prior use of antihypertensive agents: 39% diuretics

37% ACEIs

47% CCBs• Prior use of diuretic on “A” effect for new HF:

A vs C: OR 1.08 (0.53-2.21, p=0.83)

• Prior use of diuretic on “L” effect for new HF:

L vs C: OR 1.33 (0.65-2.74, p=0.44)

ALLHAT


Summary

• Patients on any prior BP med (vs. none) were at higher risk of developing HF.

• No evidence for any statistically significant interaction between prior drug type (e.g., diuretic) and treatment effect for HF, overall or during the first year

• These findings suggest that the type of BP drug at entry is not a major determinant of the HF results.

ALLHAT


2. How accurate is the diagnosis of

HF?

ALLHAT

Origin of the HF Validation StudyOrigin of the HF Validation Study

HF endpoint defined as HF endpoint defined as treatedtreated in hospital or out- in hospital or out-of-hospital or fatalof-hospital or fatal

A component of combined CVD (CHD, stroke, A component of combined CVD (CHD, stroke, HF, PAD) – pre-specified secondary outcomeHF, PAD) – pre-specified secondary outcome

Systematic central review of Systematic central review of hospitalizedhospitalized HF HF events initiated in 2001, on advice of the DSMBevents initiated in 2001, on advice of the DSMB

HF endpoint defined as HF endpoint defined as treatedtreated in hospital or out- in hospital or out-of-hospital or fatalof-hospital or fatal

A component of combined CVD (CHD, stroke, A component of combined CVD (CHD, stroke, HF, PAD) – pre-specified secondary outcomeHF, PAD) – pre-specified secondary outcome

Systematic central review of Systematic central review of hospitalizedhospitalized HF HF events initiated in 2001, on advice of the DSMBevents initiated in 2001, on advice of the DSMB

ALLHAT

Einhorn PT, et al. Am Heart J 2007;153:42-53

HF Validation Study ObjectivesHF Validation Study Objectives

ALLHAT

Evaluate ALLHAT site physician-assigned diagnosesEvaluate ALLHAT site physician-assigned diagnoses

Evaluate treatment effects reported in December Evaluate treatment effects reported in December 2002 (2002 (JAMA. 2002;288:2981-2997)

Compare RRs of validated HF between randomized Compare RRs of validated HF between randomized treatment groups with RRs reported in 2002treatment groups with RRs reported in 2002

Evaluate incidence of validated HF and examine Evaluate incidence of validated HF and examine subsequent mortality rates as indicators of clinical subsequent mortality rates as indicators of clinical significance of HFsignificance of HF

Evaluate ALLHAT site physician-assigned diagnosesEvaluate ALLHAT site physician-assigned diagnoses

Evaluate treatment effects reported in December Evaluate treatment effects reported in December 2002 (2002 (JAMA. 2002;288:2981-2997)

Compare RRs of validated HF between randomized Compare RRs of validated HF between randomized treatment groups with RRs reported in 2002treatment groups with RRs reported in 2002

Evaluate incidence of validated HF and examine Evaluate incidence of validated HF and examine subsequent mortality rates as indicators of clinical subsequent mortality rates as indicators of clinical significance of HFsignificance of HF

Einhorn PT, et al. Am Heart J 2007;153:42-53

2850 hospital records for 1987 patients received.

2778 records of 1935 patients suitable for review. Centrally abstracted by cardiology fellow 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

Einhorn PT, et al. Am Heart J 2007;153:42-53.

HF*HF* 1.19 (1.07 - 1.19 (1.07 - 1.31)1.31)

Hosp/Fatal HFHosp/Fatal HF 1.10 (0.98 - 1.10 (0.98 - 1.23)1.23)

1st Documented1st Documented 1.13 (1.00 - 1.13 (1.00 - 1.28)1.28)

ALLHAT 1ALLHAT 1 1.18 (1.02 - 1.18 (1.02 - 1.36)1.36)

ALLHAT 3 (CXR)ALLHAT 3 (CXR) 1.21 (1.04 - 1.21 (1.04 - 1.40)1.40)

Framingham 1Framingham 1 1.13 (0.99 - 1.13 (0.99 - 1.30)1.30)

Framingham 2 Framingham 2 1.12 (0.99 - 1.12 (0.99 - 1.31)1.31)

Reviewers agreeReviewers agree 1.15 (1.01 - 1.15 (1.01 - 1.32)1.32)

ALLHAT HF Validation Study ACEI versus diuretic

Definition, Relative Risk and 95% Confidence Intervals

Favors Lisinopril Favors Chlorthalidone

0.50 1 2

* Pre-specified endpoint of treated in hospital or as outpatient or fatal

Percent agreement with investigator-assigned diagnosis of

HF


ALLHAT

0102030405060708090

100

ALLHAT

Fram

ingham

1

Fram

ingham

2

Rev

iewer

s

% a

gre

eme

nt

HF Outcome VerifiedClinically Significant

ALLHAT site physician diagnoses confirmed in most patients

Treatment differences based on site physician reports corroborated when applying validation criteria sets

• RRs approximating these for the HF prespecified endpoint

6-year incidence rates of validated HF events comparable to those of stroke (5.6%) and to about half of non-fatal MI+CHD deaths (11.4%)

High mortality rates subsequent to validated hospitalized HF (55% at 5 years)

ALLHAT


3. How important are the bloodpressure differences in the

three treatment arms?

ALLHAT

BP Results by Treatment GroupBP Results by Treatment Group

Compared to chlorthalidone:

SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg, and in blacks ~4 mm Hg)

Compared to chlorthalidone:

DBP significantly lower in the amlodipine group (~1 mm Hg).

ALLHAT

BP Differences

Adjustment for follow-up SBP as time-dependent covariates in a Cox regression model only slightly modified the relative risks

– Amlodipine/chlorthalidone 2.22 2.16 first year, 1.22 1.18 after 1 year

– Lisinopril/chlorthalidone 2.08 2.01 first year, 0.96 0.93 after 1 year

ALLHAT


Exposure to different rates of BP ReductionExposure to different rates of BP Reduction

Early, inadequate blood pressure responses are Early, inadequate blood pressure responses are never fully corrected (ALLHAT, Syst-Eur, SCOPE, never fully corrected (ALLHAT, Syst-Eur, SCOPE, ASCOT, VALUE)ASCOT, VALUE)

The comparator was never able to catch up to the The comparator was never able to catch up to the active drug after short differences in initial BP active drug after short differences in initial BP despite attempts to increase therapy.despite attempts to increase therapy.

TimeTime

Benefit-Differences Persists Over TimeBenefit-Differences Persists Over Time

What we don’t and never will know!What we don’t and never will know!

• • 24 hour blood pressure ?24 hour blood pressure ?

• • Night time blood pressure ?Night time blood pressure ?

• • Central blood pressure ?Central blood pressure ?

ALLHAT

4. How can differences insecondary endpoints be termed significant

when primary endpointsare equal in all three

treatment arms?

ALLHAT

Drug comparisons for HF

• Chlorthalidone vs Amlodipine: RR 1.35 (95% CI 1.21-1.50, p<0.0013)

and consistent with external data:

Meta-analysis: RR 1.30 (1.21-1.47) in favor of Diuretics/ß blocker over CCBs for preventing HF. (BPLTT Collaboration Lancet, 2003;362:1527)

• Chlorthalidone vs Amlodipine: RR 1.35 (95% CI 1.21-1.50, p<0.0013)


Meta-analysis: RR 1.30 (1.21-1.47) in favor of Diuretics/ß blocker over CCBs for preventing HF. (BPLTT Collaboration Lancet, 2003;362:1527)

Yusuf SY, Circulation 2006;113:2166

ALLHAT

Drug comparisons for HF

• Chlorthalidone vs lisinopril: HF RR 1.19 (95% CI 1.07-1.31), p<0.001 ―Pre-specified endpoint of treated in hospital or as outpatient or fatal (Einhorn PT, et al. Am Heart J 2007;153:42-53)


Network meta–analysis: RR 0.88 (0.80-0.96) p<0.01 inNetwork meta–analysis: RR 0.88 (0.80-0.96) p<0.01 infavor of a diuretic over ACEI for preventing HF. favor of a diuretic over ACEI for preventing HF. (Psaty BM, et al. JAMA 2003;289:2534-2544)(Psaty BM, et al. JAMA 2003;289:2534-2544)

ALLHAT

Final ConclusionsFinal Conclusions

Chlorthalidone was superior to amlodipine in Chlorthalidone was superior to amlodipine in both time periods in preventing HF in the both time periods in preventing HF in the aggregate and in all subgroups: age, race, aggregate and in all subgroups: age, race, sex, diabetic history.sex, diabetic history.

Chlorthalidone was superior to lisinopril in Chlorthalidone was superior to lisinopril in preventing HF during the first year of preventing HF during the first year of treatment; thereafter, the 2 drugs were equally treatment; thereafter, the 2 drugs were equally effective in preventing HF. effective in preventing HF.

The ALLHAT studies confirmed that thiazide-The ALLHAT studies confirmed that thiazide-type diuretics should be a preferred first-step type diuretics should be a preferred first-step drug treatment for prevention of HF in high-risk drug treatment for prevention of HF in high-risk patients with hypertension and/or post MI.patients with hypertension and/or post MI.

Chlorthalidone was superior to amlodipine in Chlorthalidone was superior to amlodipine in both time periods in preventing HF in the both time periods in preventing HF in the aggregate and in all subgroups: age, race, aggregate and in all subgroups: age, race, sex, diabetic history.sex, diabetic history.

Chlorthalidone was superior to lisinopril in Chlorthalidone was superior to lisinopril in preventing HF during the first year of preventing HF during the first year of treatment; thereafter, the 2 drugs were equally treatment; thereafter, the 2 drugs were equally effective in preventing HF. effective in preventing HF.

The ALLHAT studies confirmed that thiazide-The ALLHAT studies confirmed that thiazide-type diuretics should be a preferred first-step type diuretics should be a preferred first-step drug treatment for prevention of HF in high-risk drug treatment for prevention of HF in high-risk patients with hypertension and/or post MI.patients with hypertension and/or post MI.

ALLHAT

What constitutesoptimal treatment of

ACC/AHA stage A or B HF to prevent progression

to stage C—overt symptomatic HF?

Postscript:

Heart Failure: Causal Mechanisms

Vasan RS and Levy D. Archives Int Med 1996

LVHDiastolic

DysfunctionObesityDiabetes

MI SystolicDysfunction

HF

SmokingDyslipidemia

Diabetes

Hypertension

Normal LV Structure and Function

LV Remodeling Subclinical LVDysfunction

Overt Heart Failure

ACC/AHA Stage A Stage B Stage C

Current ACC/AHA Guidelines: Management of HF as Applied to ALLHAT Patients

• ALLHAT patients were divided between stage A and B categories (Stage C patients were excluded).

• For the stage A patients (high risk without structural abnormalities), ACEIs and diuretics are recommended for treatment of HTN.

• For the stage B patients (structural heart disease), ACEIs and diuretics are recommended for treatment of HTN; ACEIs and BBs are recommended for post MI, LVH, and reduced LVEF.

• Therefore, poly-pharmacy will be necessary in the majority of patients for optimal control of HTN (Stage A and B) and for treatment of structural heart disease (Stage B).

Hunt. et al. Circulation 2005;112:1825-1852

JNC-7 Guidelines for HF Treatment

• “HF is a ‘compelling indication’ for the use of ACEI. Abundant evidence exists to justify their use with all stages of HF.”

• “Blood pressure targets in HF have not been firmly established. In most successful trials SBP were lowered to the range of 110-130 mm Hg.”

• Therefore, ACEI (or ARB)/diuretic combinations, rather than single agents, are necessary in the majority of patients for achieving ‘optimal control’ of HTN, preventing and/or reversing structural heart damage, and preventing progression to overt HF.

JNC- 7 Report. JAMA 2003;289:2560-72.

heart failure (hf) findings: are they real?

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